The DOI matches its Crossref record; 110 of the 110 references it cites were found in a registry or an index; 28 of the 67 sources its claims cite were checked for support.
Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99)
Open accessAbstract
Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer9s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP) and is specifically mediated by the β cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) as a basis for slowed LC3 turnover and the inactivation of cathepsin D and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, whereas RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one Bace1 allele from adult Ts2 mice had similar rescue effects in vivo. The modest elevation of endogenous APP-βCTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-βCTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD. SIGNIFICANCE STATEMENT Down syndrome (trisomy 21) (DS) is a neurodevelopmental disorder invariably leading to early-onset Alzheimer9s disease (AD). We showed in cells from DS individuals and neurons of DS models that one extra copy of a normal amyloid precursor protein (APP) gene impairs lysosomal acidification, thereby depressing lysosomal hydrolytic activities and turnover of autophagic and endocytic substrates, processes vital to neuronal survival. These deficits, which were reversible by correcting lysosomal pH, are mediated by elevated levels of endogenous β-cleaved carboxy-terminal fragment of APP (APP-βCTF). Notably, similar endosomal-lysosomal pathobiology emerges early in sporadic AD, where neuronal APP-βCTF is also elevated, underscoring its importance as a therapeutic target and underscoring the functional and pathogenic interrelationships between the endosomal-lysosomal pathway and genes causing AD.
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TL;DR
Lysosomal dysfunction in Down syndrome (DS) fibroblasts and Ts2 mouse neurons requires an extra APP gene copy and is mediated by APP-βCTF (C99). The defect is driven by impaired lysosomal acidification, which inactivates acid hydrolases such as cathepsin D and slows autophagic/endocytic substrate degradation.
Key findings
- DS fibroblasts showed elevated lysosomal pH (5.03 ± 0.08 vs 4.66 ± 0.06 in 2N; ~0.6 units higher) and more than eightfold more poorly acidified autolysosomes (9.24 ± 1.23% vs 1.13 ± 0.41% of total autolysosomes).
- Lysosomal cathepsin D (CTSD) activity was reduced by 45% in situ in DS fibroblasts, and CTSD specific activity was less than half that in 2N cells, despite 2.5-fold more mature 32 kDa CTSD protein.
- Lowering APP with siRNA or inhibiting BACE1 rescued lysosomal pH and CTSD deficits in DS fibroblasts and Ts2 neurons; deleting one Bace1 allele in Ts2 mice restored brain CTSD activity.
- Raising APP-βCTF in 2N fibroblasts with γ-secretase inhibition or mCherry-C99 transfection reproduced lysosomal pH elevation and reduced CTSD activity, while BACE1 inhibition ameliorated the DS phenotype.
Methods
- Primary human foreskin fibroblasts from individuals with DS and age-matched diploid controls, plus primary cortical neurons from Ts2 DS model mice and adult Ts2 mouse brain homogenates.
- Lysosomal function was assessed by [³H]-leucine long-lived protein degradation, LysoSensor Yellow/Blue dextran pH measurement, mRFP-eGFP-LC3 autophagic flux imaging, BODIPY FL-Pepstatin A and Magic Red CatB activity assays, in vitro enzyme activity assays, EM, immunoblotting, immunocytochemistry, and RNA-Seq.
- Interventions included APP siRNA, BACE1 inhibitor IV, γ-secretase inhibitor L-685,458, acidic nanoparticles (NP3), and BACE1 heterozygous crossing; statistics used two-tailed unpaired t tests or one-way ANOVA with Tukey’s post hoc analysis.
Limitations
- The paper states that its conclusion does not exclude possible additional influences of other triplicated chromosome 21 genes or metabolic factors such as oxidative stress, lipid peroxidation, and protein nitration.
- Several mechanistic claims about APP-βCTF interaction with the vATPase V0a1 subunit and impaired vATPase assembly are described as unpublished observations, not fully reported in this paper.
- Evident from the text: the main human evidence comes from primary fibroblasts rather than human brain tissue, and much of the neuronal evidence comes from cultured Ts2 mouse neurons or mouse brain homogenates, so direct human neuronal in vivo validation is not provided.
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Claims the paper makes
72 Own result · 30 Own interpretation · 13 Partly supported · 7 Sources not found · 5 Not checked yet · 5 No basis given · 4 Supported · 4 No full text of the sources · 2 Supported so far · 2 Own method · 1 Mixed support · accuracy not yet measured
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In the paper
“which boosts APP-CTF levels by inhibiting its cleavage (Fig. 5 A, B) (Jiang et al., 2010;Lauritzen et al., 2016;Hung and Livesey, 2018).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
What the sources say
- Not matchedcites Jiang et al., 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Lauritzen et al., 2016 sourceExperimental — accuracy not yet measured
The Results section (Fig. 5a; page unavailable) reports that the γ-secretase inhibitor ELND006 increased C99, an APP-βCTF. This supports the general effect of inhibiting its cleavage, but the paper does not identify or test L685,458, so it does not establish the claim for that specific compound. (LLM, conf=0.84)
- Partly supportedcites Hung and Livesey, 2018 sourceExperimental — accuracy not yet measured
The Results section (‘Gamma-Secretase Inhibition Disrupts Function of the Lysosomal-Autophagic System in Human Neurons’; page not provided) reports that inhibiting γ-secretase prevents β-CTF turnover and markedly increases β-CTF levels. But the Methods name DAPT as the γ-secretase inhibitor used, not L685,458, so this paper does not establish the claim for that specific compound. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Not matched
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“our RNA-Seq analyses, combined with previously published RNA-Seq data (Letourneau et al., 2014;Sullivan et al., 2016), showed transcript levels for the analyzed acid hydrolases to be comparable in 2N and DS fibroblasts”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
What the sources say
- Not checked — no full text of the sourcecites Letourneau et al., 2014 source
- Supportedcites Sullivan et al., 2016 source
In the Results section, Sullivan et al. report RNA-seq data comparing euploid (D21) and trisomy 21 (T21) human fibroblasts. The citation identifies previously published data used in the citing authors’ combined analysis; it does not attribute the acid-hydrolase comparison to Sullivan et al. alone. (LLM, conf=0.87)
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Extensive characterization of adult Ts2 mice (Kaur et al., 2014;Hamlett et al., 2016;Jiang et al., 2016) has documented neuropathological abnormalities equivalent in type and onset to those in the Ts65Dn trisomy model of DS”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
What the sources say
- Partly supportedcites Kaur et al., 2014 sourceExperimental — accuracy not yet measured
The Animals section reports that Ts2 mice were studied at 8 months, and the Discussion documents hippocampal glutamatergic and synaptic abnormalities. The Introduction describes synaptic plasticity and neurotransmitter abnormalities in Ts65Dn mice, but the paper does not establish that the two models’ neuropathological abnormalities are equivalent in type or onset; it compares Ts2 with disomic controls, not Ts65Dn. (LLM, conf=0.85)
- Not matchedcites Hamlett et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Jiang et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Increased APP-CTF has been linked to lysosomal degradation defect seen in the neurons derived from individuals with DS (Ts21) or familial AD with APP mutation (Hung and Livesey, 2018).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
What the sources say
- Supportedcites Hung and Livesey, 2018 source
The Results section on β-secretase inhibition (page not provided) reports that reducing APP-βCTF improved the degradative phase of autophagy in both familial AD and trisomy 21 neurons. The Discussion (page not provided) also links APP-βCTF accumulation to lysosome-autophagy dysfunction in APP-mutant neurons. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The findings support an emerging concept that acidification impairment may be a proximal biochemical event in AD, common to multiple genetic risk factors that cause or promote AD (Lee et al., 2010;Xue et al., 2014;Vidoni et al., 2016).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Partly supportedcites Lee et al., 2010 sourceExperimental — accuracy not yet measured
The Discussion (page not available in our copy) links impaired lysosomal acidification to PS1 mutations that cause familial AD and suggests lysosomal dysfunction may also contribute to sporadic AD. It does not establish that acidification impairment is common to multiple distinct genetic risk factors for AD; its genetic findings concern PS1. (LLM, conf=0.87)
- Partly supportedcites Xue et al., 2014 sourceExperimental — accuracy not yet measured
The Abstract and the section “CRND8 Glia Exhibit Lysosomal Dysfunction, Which Is Reversed by SWNT” link mutant APP in an AD mouse model to lysosomal dysfunction, and the Figure 1 description suggests that restoring lysosomal acidification may improve proteolysis (page numbers unavailable). The paper does not establish acidification impairment as a proximal event in AD or show that it is common to multiple genetic risk factors; it studies glia from one mutant-APP mouse model. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites Vidoni et al., 2016 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“Lysosomal pH and CTSD activity are similarly, impaired in primary glia cultured from brains of a mutant APP model of AD (CRND8) (Xue et al., 2014).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Partly supportedcites Xue et al., 2014 sourceExperimental — accuracy not yet measured
In “CRND8 Glia Exhibit Lysosomal Dysfunction, Which Is Reversed by SWNT” (page unavailable), the paper reports markedly decreased active cathepsin D in primary CRND8 glia. It also reports impaired CatD maturation and discusses lysosomal acidification, but the available passages do not establish impaired lysosomal pH as a separate finding. (LLM, conf=0.83)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“a process optimally requiring an intralysosomal pH of ϳ4.0 -4.5 (Barrett, 1970;Cunningham and Tang, 1976).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Partly supportedcites Barrett, 1970 sourceExperimental — accuracy not yet measured
The paper identifies cathepsin D as a lysosomal enzyme and reports that its activity depends on acidic pH. In the section on pH effects (page unavailable), however, the measured activity optima are about 3.5 for human and 3.0 for chicken cathepsin D under the assay conditions. It does not establish that activation inside lysosomes optimally requires pH 4.0–4.5. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites Cunningham and Tang, 1976 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/ lysosomes.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“whereas RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/ lysosomes.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) as a basis for slowed LC3 turnover”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The Ts2 mouse model's lysosomal deficits are representative of human Down syndrome.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and higher in situ activity in lysosomes of intact DS cells using Magic Red CatB substrate”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Other lysosomal hydrolases optimally active at low pH, including lysosomal acid phosphatase (ACP2) (Gieselmann et al., 1984; Ashtari et al., 2016) and -hexosaminidase A (HEXA) (Wendeler and Sandhoff, 2009), were similarly significantly less active in DS fibroblasts”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Deleting one Bace1 allele from adult Ts2 mice had similar rescue effects in vivo.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: BACE1 inhibition reduces cathepsin deficits specifically by lowering APP-βCTF, not through other BACE1 substrates.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We confirmed the accumulation of APP-CTF in the lysosomes in mCherry-C99 transfected cells incubated with dextran-Alexa-488 to mark lysosomes (Fig. 5J ).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Using antibody JRF/AN/25 specific for CTF (Mathews et al., 2002) and anti-CTSD antibody from Scripps, we observed greater APP-CTF colocalization with CTSD (Pearson's correlation coefficient) in DS fibroblasts (Fig. 5 A, B; F (3,59) ϭ 25.21, p Ͻ 0.0001; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“CTSB activities were not altered by this stage of neuronal development (Fig. 6F-H; t (8) ϭ 0.467, p ϭ 0.653; unpaired t test).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“although CTSD protein did not accumulate (Fig. 6 I, J; t (7) ϭ 0.375, p ϭ 0.719; unpaired t test)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In Ts2 neurons, APP downregulation normalized the sizes of enlarged EEA1-positive early endosomes without affecting 2N endosomes (Fig. 7 D, E; F (3,174) ϭ 8.849, p Ͻ 0.0001 for size 0.01-0.5 m 2 ; F (3,174) ϭ 15.98, p Ͻ 0.0001 for size 0.51-1.4m 2 ; F (3,174) ϭ 12.66, p Ͻ 0.0001 for size 1.41-3.0m 2 ; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The intensity of BODIPY FL (BP) fluorescence after cells were incubated with BODIPY FL-Pepstatin A for 30 min revealed a 45% reduction in the level of CSTD activity in the lysosomes of intact DS fibroblasts compared with that in 2N control cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“lowering APP expression using siRNA diminished APP protein levels significantly in both Ts2 and 2N neuronal cultures (Fig. 7A-C; F (3,45) ϭ 67.19, p Ͻ 0.0001; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“primary cultures of cortical neurons from Ts2 mice, despite their immaturity, develop the typical AD-related enlargement of early (Fig. 6 A, B; t (116) ϭ 4.550, p Ͻ 0.0001 for size 0.01-0.5 m 2 ; t (116) ϭ 5.617, p Ͻ 0.0001 for size 0.51-1.4m 2 ; t (110) ϭ 5.175, p Ͻ 0.0001 for size 1.41-3.0m 2 ; unpaired t test)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“quantitative immunoblot analysis showed that maturation of CTSD was not impaired in DS fibroblasts”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which had 2.5-fold more mature form of 32 kDa CTSD protein than 2N cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Greater numbers and sizes of lysosomes in DS fibroblasts were also seen after long pulse-chase (4 h pulse and 20 h chase) of dextran-AlexaFluor-546”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Lysosomal pH was significantly higher in DS fibroblasts than in 2N cells (pH ϭ 5.03 Ϯ 0.08 vs 4.66 Ϯ 0.06, t (92) ϭ 8.414, p Ͻ 0.0001; unpaired t test).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Lysosomal acidification deficiency in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CTSD activation in lysosomes in situ (Fig. 6 E, G; t (95) ϭ 2.373, p ϭ 0.019 for CTSD; t (70) ϭ 0.252, p ϭ 0.802 for CTSB; unpaired t test) and total activity in vitro are significantly lowered compared with levels in 2N neurons”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Ts2 neurons, APP downregulation normalized the sizes of enlarged EEA1-positive early endosomes without affecting 2N endosomes (Fig. 7 D, E; F (3,174) ϭ 8.849, p Ͻ 0.0001 for size 0.01-0.5 m 2 ; F (3,174) ϭ 15.98, p Ͻ 0.0001 for size 0.51-1.4m 2 ; F (3,174) ϭ 12.66, p Ͻ 0.0001 for size 1.41-3.0m 2 ; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, in 2N fibroblasts, transient transfection of a fluorescence-tagged CTF (mCherry-C99) significantly reduced in situ CTSD activity in 2N cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Transient transfection of mCherry-C99 raises APP-βCTF levels without itself causing lysosomal defects independent of βCTF.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the activity of CTSB, a lysosomal protease that is stable and optimally active in the pH range of 6.0 -6.5 (Linebaugh et al., 1999), exhibited higher in vitro activity at the less acidified pH range of DS lysosomes than at the lower pH of lysosomes in 2N cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“AZD treatment for 2 h elevated LC3-II in DS cells to levels significantly higher than those in 2N fibroblasts (Fig. 1 E, F; t (10) ϭ 6.570, p Ͻ 0.0001; unpaired t test).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lowering APP levels also restored normal levels of in situ lysosomal CTSD activation (Fig. 7 F, G; F (3,140) ϭ 19.24, p Ͻ 0.0001; one-way ANOVA)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and suppressed lysosomal in situ CTSD activity to the levels in DS cells (Fig. 5 F,G;F (3,508) ϭ 98.19, p Ͻ 0.0001; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By contrast, blocking APP-CTF production using BACE1 inhibitor IV (10 M) for 24 h had no effect on the lysosomal pH of 2N fibroblasts (Fig. 5E)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: BACE1 inhibitor IV at 10 µM for 24 h specifically blocks APP-βCTF production without affecting lysosomal pH through off-target mechanisms.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We find that exposure of DS fibroblasts to cyclodextrin, which promotes cholesterol efflux from lysosomes (Peake and Vance, 2012), lowers both lysosomal cholesterol, and GlcCer levels and reduces CTSD accumulation (E.I., J.Y., and R.A.N., unpublished observations).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results showed that, even in the absence of APP gene triplication or a trisomic chromosome 21, raising APP-CTF in 2N cells induced a significant rise in the pH of lysosomes (Fig. 5E; F (3,32) ϭ 18.93, p Ͻ 0.0001; one-way ANOVA) equal to that in DS lysosomes”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, higher levels of CTSD and CTSB protein in DS fibroblasts could not be explained by increased transcription of their mRNA”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and late endosomes (Fig. 6C; t (117) ϭ 2.649, p ϭ 0.0092 for size 1.41-3.0m 2 ; unpaired t test)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Quantitative immunoblot analyses confirmed that levels of APP-CTF were higher in the enriched lysosome fractions from DS fibroblasts than in the corresponding fractions from 2N cells (Fig. 5C,D; F (3,12) ϭ 67.37, p Ͻ 0.0001 in total lysate; F (3,12) ϭ 8.314, p ϭ 0.0029 in lysosome; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The addition of protease inhibitors leupeptin and pepstatin A (LP) (Ivy et al., 1989;Chen et al., 2000) to AZD-treated DS and 2N cells equalized LC3-II levels in the two cell lines”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment of the cells with a combination of lysosomal proteolysis inhibitors, NH 4 Cl (20 mM) and leupeptin (100 M) (NL), eliminated proteolytic rate differences between 2N and DS”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: BACE1 inhibition reduces cathepsin deficits specifically by lowering APP-βCTF, not through other BACE1 substrates.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“concurrent with an enlargement of endosomes revealed by a short pulse-chase (10 min-10 min) of dextran-AlexaFluor-488”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“EM images taken 24 h after endocytic uptake of HRP revealed greater accumulation of HRP in lysosomes of DS cells than in 2N cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Incubations with 1 mg/ml NP3 nanoparticles for 24 h restored in situ CTSD enzyme activity fully in DS cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DS fibroblasts at baseline had more than an eightfold higher percentage of poorly acidified ALs than detected in 2N fibroblasts (9.24 Ϯ 1.23% vs 1.13 Ϯ 0.41%) relative to the total AL population”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Lysosomal acidification deficiency in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but as expected, the lysosomal pH deficit in DS fibroblasts was ameliorated (Fig. 5E; F (3,34) ϭ 15, p Ͻ 0.0001; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: BACE1 inhibitor IV at 10 µM for 24 h specifically blocks APP-βCTF production without affecting lysosomal pH through off-target mechanisms.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We find that exposure of DS fibroblasts to cyclodextrin, which promotes cholesterol efflux from lysosomes (Peake and Vance, 2012), lowers both lysosomal cholesterol, and GlcCer levels and reduces CTSD accumulation (E.I., J.Y., and R.A.N., unpublished observations).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and even higher APP-CTF (3.3-fold; t (6) ϭ 2.814, p ϭ 0.0306; unpaired t test) protein levels (Fig. 6 I, J ).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“primary Ts2 neurons at DIV 7 showed commensurately higher APP (1.7fold; t (6) ϭ 3.402, p ϭ 0.0145; unpaired t test)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and further lowered CSTD activity in DS fibroblasts (Fig. 5 H, I; transfected cell circled; F (3,364) ϭ 77.21, p Ͻ 0.0001; oneway ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Transient transfection of mCherry-C99 raises APP-βCTF levels without itself causing lysosomal defects independent of βCTF.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activity in vitro are significantly lowered compared with levels in 2N neurons (Fig. 6H; t (4) ϭ 4.216, p ϭ 0.0135; unpaired t test)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: BACE1 inhibition reduces cathepsin deficits specifically by lowering APP-βCTF, not through other BACE1 substrates.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, lysosomal proteolysis rate is lowered in DS fibroblasts, and multiple lysosomal proteases in addition to CTSD with highly acidic pH optima are partially inhibited, consistent with a key role of lysosomal pH change.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, DS cells also showed reduced capacity to eliminate damaged mitochondria in response to mitochondrial depolarization by carbonyl cyanide m-chlorophenyl hydrazone (Bordi et al., manuscript submitted).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“BACE1 gene dosage reduction upon crossing TS2 mice with BACE ϩ/Ϫ mice restored CTSD activity to the normal level seen in the 2N brain homogenates (Fig. 7H; F (2,10) ϭ 10.70, p ϭ 0.0074; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, lysosomal proteolysis rate is lowered in DS fibroblasts, and multiple lysosomal proteases in addition to CTSD with highly acidic pH optima are partially inhibited, consistent with a key role of lysosomal pH change.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Other lysosomal hydrolases optimally active at low pH, including lysosomal acid phosphatase (ACP2) (Gieselmann et al., 1984; Ashtari et al., 2016) and -hexosaminidase A (HEXA) (Wendeler and Sandhoff, 2009), were similarly significantly less active in DS fibroblasts”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“sizes of lysosomes quantified after dextran-AlexaFluor-546 uptake, were larger in untreated DS cells than in 2N cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“specific activity of CSTD in DS fibroblasts was less than half that in 2N cells”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The 2N and DS fibroblasts are comparable except for trisomy 21.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This colocalization increased signifi-cantly in both DS and 2N cells when the fibroblasts were treated with ␥-secretase inhibitor L685,458, which boosts APP-CTF levels by inhibiting its cleavage (Fig. 5 A, B) (Jiang et al., 2010;Lauritzen et al., 2016;Hung and Livesey, 2018).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We further established that lysosomal pH is abnormally elevated (Fig. 6D; t (14) ϭ 4.918, p ϭ 0.0002; unpaired t test)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“total activity in vitro are significantly lowered compared with levels in 2N neurons (Fig. 6H; t (4) ϭ 4.216, p ϭ 0.0135; unpaired t test)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
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“Finally, CTSD specific activity was lowered in brain homogenates from 8-month-old Ts2 mice (Fig. 7H; F (2,10) ϭ 10.70, p ϭ 0.0074; one-way ANOVA).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
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In the paper
“AZD treatment elevated lysosomal size in both 2N and DS fibroblasts”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
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“Lysosomal acidification deficiency in DS fibroblasts.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“CTF dependence of lysosomal CTSD activity in 2N and DS fibroblasts.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“We observed that, in addition to CTSD, acid hydrolases acting on lipids, lipoproteins, and glycoproteins are also partially inactivated, suggesting even broader metabolic dysfunction in DS lysosomes than just proteolysis.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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“We have identified a direct physical interaction of lysosomal-associated APP-CTF with the cytosol-exposed domain of the transmembrane V0a1 subunit of the vATPase.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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“Regulation of CTSD activity in 2N and DS fibroblasts by downregulation of APP.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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“Accumulation of CTF in lysosome of DS fibroblast”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“That these effects in DS are demonstrable in the authentic trisomy 21 disorder, rather than in only genetically manipulated model systems”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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“Endosomal and lysosomal defects in Ts2 mouse cortical neuronal culture.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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“We discovered that luminal acidification of lysosomes is significantly impaired in DS”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“Restoration of endosomal and lysosomal defects in Ts2 mice.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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“Notably, CTSB, a lysosomal exopeptidase with a pH optimum in the mildly acidic range (Barrett and Kirschke, 1981), was more active in DS lysosomes.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Barrett and Kirschke, 1981 source
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In the paper
“In any event, lysosomal turnover of both autophagic and endocytic substrates was deficient in DS cells.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“Abnormally elevated lysosomal pH in both DS fibroblasts and primary cortical neurons from Ts2 mice was sufficient to depress CTSD activation”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“Restoration of endosomal and lysosomal defects in Ts2 mice.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“That substrate accumulation worsened after strong induction of mTOR-dependent autophagy is notable”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“In any event, lysosomal turnover of both autophagic and endocytic substrates was deficient in DS cells.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
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In the paper
“as a basis for slowed LC3 turnover and the inactivation of cathepsin D and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
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In the paper
“Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) as a basis for slowed LC3 turnover”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
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In the paper
“and is specifically mediated by the  cleaved carboxy terminal fragment of APP (APP-CTF, C99).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
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- Rests on an assumption: BACE1 inhibition reduces cathepsin deficits specifically by lowering APP-βCTF, not through other BACE1 substrates.
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In the paper
“These results are consistent with deficient lysosomal acidification being a major basis for CTSD activity deficits in DS cells.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Altered lysosomal enzymatic activity in DS fibroblasts
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In the paper
“the higher LC3-II levels in AZD-treated DS fibroblasts than in treated 2N cells were due to impaired lysosomal degradation.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
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In the paper
“demonstrating that the proteolysis deficit in DS fibroblasts is a result of selectively impaired lysosomal degradation.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
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In the paper
“The findings reinforce the concept that the causal effects of App in driving AD depends on a range of metabolites generated in the Endosomal-Lysosomal system (ELS), including APP-CTF, which are capable of disrupting ELS function.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Introduction
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In the paper
“Thus, lysosomal deficits, like previously described anomalies of endosomes (Jiang et al., 2010) and exosomes (Perez-Gonzalez et al., 2012;Gauthier et al., 2017), are interrelated pathobiology at the earliest phase of AD linked to a common proximal genetic factor.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Introduction
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In the paper
“suggesting that stress conditions in cultures can be permissive for earlier onset of endosomal pathology.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
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In the paper
“The modest elevation of endogenous APP-CTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-CTF, but not APP, is also elevated.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
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In the paper
“implying APP-dependent lysosomal impairment.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
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In the paper
“suggesting that the rates of autophagosome (AP) formation were similar when autophagy is strongly induced”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
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In the paper
“and that a rise in levels of APP-CTF in lysosomes is the most proximal molecular cause of the disruption.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“Therefore, lysosomal functional defects may be the consequence of pathological accumulation of CTF in lysosome.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
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- Rests on an assumption: Transient transfection of mCherry-C99 raises APP-βCTF levels without itself causing lysosomal defects independent of βCTF.
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In the paper
“The toxic effects of APP triplication on lysosomes in DS are due mainly to APP-CTF”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
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- Rests on an assumption: Lysosomal abnormalities in DS fibroblasts are representative of the toxic effects of APP triplication on lysosomes in DS.
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In the paper
“showing that endocytic cargoes reaching lysosomes in DS cells persisted there longer.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In our study, lysosomal proteolysis rate is lowered in DS fibroblasts, and multiple lysosomal proteases in addition to CTSD with highly acidic pH optima are partially inhibited, consistent with a key role of lysosomal pH change.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
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In the paper
“The signature AD-related endosome enlargement develops by 2-3 months after birth in both mouse models (Jiang et al., 2016)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Cultured primary neurons from DS model mice exhibit the endosomal and lysosomal abnormalities seen in DS fibroblasts
What the sources say
- Not matchedcites Jiang et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Abstract
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In the paper
“Our findings show that modest elevation of endogenous APP in DS is sufficient to induce lysosomal disruption”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“The restoration of CTSD activation in DS lysosomes by targeted acidic nanoparticles indicated that defective acidification in DS is the primary basis for the impaired activities of multiple acid hydrolases with exceptionally low pH optima.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“We observed that, in addition to CTSD, acid hydrolases acting on lipids, lipoproteins, and glycoproteins are also partially inactivated, suggesting even broader metabolic dysfunction in DS lysosomes than just proteolysis.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“and primarily responsible for disrupting lysosomal hydrolase activities and CTSD protein buildup.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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In the paper
“APP-CTF-Dependent Lysosomal Dysfunction in Down Syndrome”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Competition by APP-CTF with specific V1 subunits for binding to the V0a1 subunit impedes association of the V1 and V0 sectors of the complex.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our findings indicate that APP-CTF elevation is necessary and sufficient to impair lysosomal function in the context of DS”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“when APP-CTF levels are artificially raised, even in control 2N cells.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our findings indicate that APP-CTF elevation is necessary and sufficient to impair lysosomal function in the context of DS”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 16
- Probably not a substantial claim. 23
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“a disorder in which an early onset form of AD invariably develops due mainly to a third copy of APP present on trisomic chromosome 21 (Korbel et al., 2009;Doran et al., 2017;Colacurcio et al., 2018).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Introduction
What the sources say
- Disputedcites Korbel et al., 2009 sourceExperimental — accuracy not yet measured
The Results and Discussion links increased Alzheimer’s disease risk in Down syndrome to increased APP copy number, but it does not say the disease develops invariably. It describes a 65-year-old subject with Down syndrome who had neither dementia nor amyloid accumulation, contrary to the claim of inevitable early-onset disease. Page numbers are not supplied in our copy. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
- Partly supportedcites Doran et al., 2017 sourceExperimental — accuracy not yet measured
The Introduction links APP triplication in Down syndrome to increased brain amyloid, and the Discussion describes increased APP copy number as central to AD pathogenesis. But the Introduction distinguishes ubiquitous AD-like neuropathology from dementia: dementia prevalence varies from 30–75% at age 65. The paper therefore does not support the claim that early-onset AD invariably develops. (LLM, conf=0.90)
- Partly supportedcites Colacurcio et al., 2018 sourceExperimental — accuracy not yet measured
The Introduction says that almost all people with Down syndrome who reach age 40 develop AD neuropathology, and that the increased risk is mainly attributable to the extra copy of APP on chromosome 21. It does not say AD invariably develops: it describes APP triplication as necessary but not necessarily sufficient, and says dementia approaches 100% by age 70 rather than reaching it. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Disputed
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Emerging genetic, neuropathological, and biological evidence implicates dysfunction of the endosomal-lysosomal pathway in AD pathogenesis at early and late stages of disease (Nixon, 2017) as well as in other late-onset neurodegenerative diseases (Nixon, 2013;Stoka et al., 2016;Vidoni et al., 2016;Colacurcio et al., 2018).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Nixon, 2017 source
- Not checked — no full text of the sourcecites Nixon, 2013 source
- Supportedcites Stoka et al., 2016 source
Stoka et al. is cited for the clause about other late-onset neurodegenerative diseases, not the earlier clause about stages of Alzheimer’s disease. Section 6.3 (page unavailable) describes Parkinson’s disease as affecting older adults and reports that reduced cathepsin D activity impaired lysosomal function and promoted α-synuclein aggregation. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Protein constituents of lysosomes, such as progranulin (Beel et al., 2017) and NPC1 (Liao et al., 2007;Macías-Vidal et al., 2016), also interact directly with CTSD, influencing its activity, stability, and conceivably turnover rate.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
What the sources say
- Supportedcites Beel et al., 2017 source
The Results section reports strong evidence that progranulin interacts directly with CTSD, and the Discussion says progranulin stabilizes CTSD and increases its proteolytic activity. The cited paper is attached to progranulin, not NPC1. The sentence presents an effect on turnover only as conceivable, consistent with the reported effect on stability. (LLM, conf=0.90)
- Partly supportedcites Liao et al., 2007 sourceExperimental — accuracy not yet measured
The sections on increased cathepsin D levels and early-onset lysosomal abnormality report higher cathepsin D levels and activity in Npc1−/− mouse brains (page not provided). They do not show that NPC1 interacts directly with CTSD or affects its stability or turnover. Progranulin is supported by a separate citation, not the one audited here. (LLM, conf=0.88)
- Not matchedcites Macías-Vidal et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“CTSD protein levels are elevated in CTSB/CTSL double KO mice (Felbor et al., 2002), suggesting intralysosomal CTSD proteolysis, even though the involved protease(s) are unclear.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
What the sources say
- Supportedcites Felbor et al., 2002 source
The Results section (‘Procathepsin D and Cathepsin D Are Increased in Cathepsin B−/−/L−/− Brains’; page not available) reports a proportional increase in both forms of cathepsin D in double-knockout brains. The cited claim accurately summarizes that protein-level finding; the subsequent suggestion about intralysosomal proteolysis is the citing authors’ inference. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in familial AD caused by presenilin 1 (PSEN1) mutations, failed lysosomal delivery of the V0a1 subunit markedly impairs lysosomal acidification, inducing acid hydrolase inhibition and lysosomal substrate buildup in patient primary fibroblasts ( Lee et al., 2010 ( Avrahami et al., 2013).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Partly supportedcites Lee et al., 2010 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not matchedcites Avrahami et al., 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CTSD is a ubiquitous protease, but its unique importance in brain is illustrated by the relatively selective neurodevelopmental and progressive neurodegenerative phenotype induced by the loss-of-function CTSD mutations causing the congenital disorder neuronal ceroid lipofuscinosis CLN10 (Tyynela ¨et al., 2000;Siintola et al., 2006).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Partly supportedcites Tyynela ¨et al., 2000 sourceExperimental — accuracy not yet measured
The Results describe a loss-of-function cathepsin D mutation in sheep with severe brain pathology at birth, while other examined organs appeared macroscopically unaffected; the Discussion calls brain pathology the most striking feature. But this paper does not establish that CTSD mutations cause human CLN10: its Discussion says that whether congenital human NCL represents cathepsin D deficiency remains to be determined. (LLM, conf=0.86)
- Not matchedcites Siintola et al., 2006
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the abnormally high level of mTOR activation seen in the brains of DS mouse models (Iyer et al., 2014;Perluigi et al., 2014) and in DS fibroblasts (Bordi et al., manuscript submitted)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Iyer et al., 2014 source
- Partly supportedcites Perluigi et al., 2014 sourceExperimental — accuracy not yet measured
The Results section (mTOR activation and inhibition of autophagosome formation; page unavailable) reports increased mTOR phosphorylation in Down syndrome brain tissue compared with age-matched controls. The Methods identify the tissue as frontal cortex from people with Down syndrome, not mouse models. The Discussion mentions altered Akt phosphorylation in DS mouse models, but does not establish increased mTOR activation in their brains. The fibroblast claim is attached to a different citation. (LLM, conf=0.87)
- Not matchedcites Bordi et al., manuscript submitted
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mutations or imbalance of the subunits or accessory proteins composing the proton pump impair acidification and lead to neurodegeneration in numerous congenital diseases (Colacurcio and Nixon, 2016).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Supportedcites Colacurcio and Nixon, 2016 source
Section 2.1 (page unavailable) reports that mutations in v-ATPase subunits impair lysosomal acidification and that mutations in accessory proteins cause congenital disorders associated with neurodegeneration. It also describes reduced subunit expression and de-acidification when the assembly protein ATP6AP2 is lost. The Conclusions (page unavailable) similarly link defects in the pump and its assembly proteins to CNS neurodegeneration. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CTSD activation is deficient in various neuropathologic states and as a result of genetic mutations (Colacurcio and Nixon, 2016;Vidoni et al., 2016).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Partly supportedcites Colacurcio and Nixon, 2016 sourceExperimental — accuracy not yet measured
Section 2.2 (page unavailable) reports impaired cathepsin activation in glial cells expressing mutant APP and impaired cathepsin function or maturation in other genetic models of neurological disease. Section 1.2 identifies cathepsin D as an acid-dependent protease, but the disease passages do not establish that the impaired activation is specifically CTSD activation. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites Vidoni et al., 2016 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“APP-CTF has also been previously linked to lysosomal dysfunction in AD models involving overexpressed forms of FAD-mutated APP with or without additional overexpression of other mutated human AD genes (Lauritzen et al., 2012(Lauritzen et al., , 2016;;Yang et al., 2014;Kaur et al., 2017;Bourgeois et al., 2018), and in iPSC generated Ts21 neurons (Hung and Livesey, 2018).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Supportedcites Lauritzen et al., 2012 source
The Results report C99 accumulation in the 3xTgAD mouse model and enlarged cathepsin B-positive structures in C99-positive neurons, suggesting lysosomal dysfunction. The Discussion also links C99 accumulation to autophagolysosomal structures. The iPSC-generated Ts21 neurons are attributed to a different citation, not Lauritzen et al. (2012). Page numbers are unavailable in our copy. (LLM, conf=0.89)
- Partly supportedcites Yang et al., 2014 sourceExperimental — accuracy not yet measured
The Introduction describes lysosomal dysfunction in TgCRND8 mice overexpressing FAD-mutated human APP. The section on prevention of lysosomal lipid accumulation discusses impaired lysosomal degradation and accumulation of APP-CTFs, but does not identify APP-βCTF specifically as a cause of that dysfunction. The Ts21-neuron clause is attributed to a different citation, not Yang et al. (LLM, conf=0.84)
- Supportedcites Hung and Livesey, 2018 source
The Hung and Livesey citation is attached to the Ts21-neuron clause, not the preceding claims about overexpression models. The Results describe iPSC-derived Ts21 neurons with lysosomal deficits and report that reducing APP-βCTF production by β-secretase inhibition improved autophagy defects in those neurons (no page numbers provided). (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Lysosomal deficits in DS add to the known endosomal anomalies known to develop in DS within the same vesicular trafficking pathway, which include some signature features of early AD and are also APP-dependent and mediated by APP-CTF (Jiang et al., 2010(Jiang et al., , 2016;;Hung and Livesey, 2018).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not matchedcites Jiang et al., 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Jiang et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Hung and Livesey, 2018 sourceExperimental — accuracy not yet measured
In the Results section on early endosomes (page unavailable), the paper reports enlarged early endosomes in trisomy 21 (DS) neurons, alongside neurons with APP duplication or mutation. That supports the presence of endosomal anomalies and an association with APP, but does not establish that the DS endosomal anomalies are APP-dependent or mediated by APP-βCTF. Its β-secretase inhibition and APP-knockout results address lysosomal-autophagy defects, not the early-endosome anomalies. (LLM, conf=0.85)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CTSD is considered as a key protease in the lysosomal degradation of many pathogenic proteins in addition to APP metabolites, including ␣-synuclein and huntingtin (Kegel et al., 2000;Sevlever et al., 2008).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Partly supportedcites Kegel et al., 2000 sourceExperimental — accuracy not yet measured
The Abstract reports that huntingtin-containing vacuoles incorporated cathepsin D, and the Discussion proposes the endosomal–lysosomal pathway as a route for huntingtin removal. The paper does not establish that CTSD is a key protease responsible for degrading huntingtin, and it does not address CTSD-mediated degradation of α-synuclein or APP metabolites. Page numbers are unavailable in our copy. (LLM, conf=0.85)
- Supportedcites Sevlever et al., 2008 source
The Discussion states that cathepsin D is the main lysosomal enzyme involved in α-synuclein degradation. In the jointly cited sentence, this supports the α-synuclein example attributed to Sevlever et al.; the sentence also cites Kegel et al. for its other example. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The level of V1 sector association with the V0 sector regulates ATPase and proton pump activities of the vATPase complex on lysosomes (Cotter et al., 2015).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Supportedcites Cotter et al., 2015 source
The ‘Regulated assembly of the V-ATPase’ section says that V1–V0 assembly regulates V-ATPase activity and specifically reports that increased assembly on lysosomes promotes the low pH needed for antigen processing. The ‘Structure and mechanism’ section identifies V1 as responsible for ATP hydrolysis and V0 for proton transport, and says V1 ATPase activity is inhibited upon dissociation. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this investigation, we uncovered AD-related lysosomal functional deficits in primary fibroblasts from individuals with DS, representing the authentic trisomy 21 disorder, and in neurons from Ts2 mice modeling DS.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Impaired vATPase assembly, like the deficits reported in the present study, is rescued by specifically lowering APP-CTF levels (E.I., Y.J., R.A.N., unpublished observations).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
None of the sources cited for this claim have been checked yet.
In the paper
“Notably, BACE1 activity and APP-CTF levels are elevated in AD brain in the absence of detectable APP elevation (Holsinger et al., 2002;Pera et al., 2013;Kim et al., 2016).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Introduction
What the sources say
- Not checked — no full text of the sourcecites Holsinger et al., 2002 source
- Not matchedcites Pera et al., 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Kim et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“lysosomal alterations develop months before -amyloid deposition in AD mouse models with late-onset amyloidosis (J.H.L. and R.A.N., manuscript in preparation).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not matchedcites J.H.L. and R.A.N., manuscript in preparation
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Given that APP-CTF levels are also higher in AD brain, even though APP levels are not detectably elevated (Pera et al., 2013;Kim et al., 2016)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not matchedcites Pera et al., 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Kim et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim have been checked yet.
In the paper
“Similar CTSD changes seen in fibroblasts carrying the ATP13A2 mutation in Parkinson disease (Bourdenx and Dehay, 2016) were reversed by normalizing lysosomal pH with acidic nanoparticles”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
What the sources say
- Not checked — no full text of the sourcecites Bourdenx and Dehay, 2016 source
- Not matchedcites Bourdenx et al., 2016
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, primary DS fibroblasts represent authentic human DS genetically unmodified, in contrast to previously used genetically modified models of AD engineered by the transgenic overexpression of APP carrying FAD mutations together in some cases with other mutated AD-related human genes.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Introduction
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“Additionally, posttranslational modifications of CTSD, such as oxidation or nitration, which have been reported for CTSD in DS (Butterfield et al., 2014b), could alter its activity and increase its resistance to proteolysis, thereby promoting accumulation.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
What the sources say
- Not matchedcites Butterfield et al., 2014b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The detection of functional lysosomal abnormalities preceding the flagrant lysosomal pathology and accumulation of lysosomal content imply a proximal link to the gene most strongly implicated in AD.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Introduction
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“also exhibiting markedly lowered baseline AP formation and mitophagy, which can be restored by selectively inhibiting TORC1 and TORC2 (M.Bordi, manuscript submitted)”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not matchedcites M.Bordi, manuscript submitted
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Notably, CTSB, a lysosomal exopeptidase with a pH optimum in the mildly acidic range (Barrett and Kirschke, 1981), was more active in DS lysosomes.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Barrett and Kirschke, 1981 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Notably, even a partial loss of CTSD function is associated with CNS deficits in humans (Mamo et al., 2012;Tatti et al., 2013).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Mamo et al., 2012 source
- Not matchedcites Tatti et al., 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Lysosomal acidification is maintained principally by the vacuolar-type H ϩ -ATPase complex (vATPase), which imports hydrogen ions into the lysosome (Mindell, 2012).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Mindell, 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“This conclusion, however, does not exclude the possible additional influences of other triplicated chromosome 21 genes or metabolic factors, such as oxidative stress, lipid peroxidation, and protein nitration (Perluigi and Butterfield, 2012;Butterfield et al., 2014a), which are likely additive factors in corrupting lysosome functions.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not matchedcites Perluigi and Butterfield, 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Butterfield et al., 2014a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim have been checked yet.
In the paper
“CTSD gene transcription in neurons is upregulated at early stages of AD (Cataldo et al., 1995) and is accompanied by the accumulation of CTSD forms with decreased activity (P.S.M. and R.A.N., manuscript in preparation).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Cataldo et al., 1995 source
- Not matchedcites P.S.M. and R.A.N., manuscript in preparation
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We established deficient acidification by direct ratiometric measurement in lysosomes in situ and confirmed that ALs were incompletely acidified using an mRFP-eGFP-LC3 construct transfected into DS cells in conjunction with dextran-AlexaFluor-647 uptake.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The identification of a lysosomal acidification defect in DS and DS model neurons therefore implicates APP via its BACE1-cleaved metabolite as a second key etiologic factor in AD, together with PSEN1, in directly dysregulating vATPase.”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Ts2 mice are a valid model of Down syndrome.
In the paper
“we previously reported that ventricular CSF obtained postmortem from AD patients has substantially elevated levels of CTSD with markedly lowered specific activity compared with CSF from individuals with Huntington's disease or from non-neurologic disease controls (Schwagerl et al., 1995).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not checked — no full text of the sourcecites Schwagerl et al., 1995 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“impaired autolysosomal acidification is the earliest autophagy alteration seen in AD mouse models expressing a neuronal mRFP-eGFP-LC3 transgene and accompanies the appearance of intraneuronal APP-CTF (Lee et al., 2019) (J.H.L. and R.A.N., manuscript in preparation).”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
What the sources say
- Not matchedcites Lee et al., 2019
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites J.H.L. and R.A.N., manuscript in preparation
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
The paper relies on this without support.
The extra copy of APP is the only trisomic gene necessary for the lysosomal dysfunction in Down syndrome.
“Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP)”
The paper relies on this without support.
BACE1 inhibition reduces cathepsin deficits specifically by lowering APP-βCTF, not through other BACE1 substrates.
“Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons.”
The paper relies on this without support.
The Ts2 mouse model's lysosomal deficits are representative of human Down syndrome.
“Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells.”
The paper relies on this without support.
The 2N and DS fibroblasts are comparable except for trisomy 21.
“Human foreskin fibroblasts from DS patients and diploid age-matched controls (2N) were purchased from the Coriell Cell Repositories (AG07096, AG04823, GM04617, GM08680, AG07095, AG06922, GM08429, GM5381) and maintained according to the distributor's protocols”
The paper relies on this without support.
Lysosomal abnormalities in DS fibroblasts are representative of the toxic effects of APP triplication on lysosomes in DS.
“The toxic effects of APP triplication on lysosomes in DS are due mainly to APP-CTF”
The paper relies on this without support.
BACE1 inhibitor IV at 10 µM for 24 h specifically blocks APP-βCTF production without affecting lysosomal pH through off-target mechanisms.
“blocking APP-CTF production using BACE1 inhibitor IV (10 M) for 24 h had no effect on the lysosomal pH of 2N fibroblasts (Fig. 5E), but as expected, the lysosomal pH deficit in DS fibroblasts was ameliorated (Fig. 5E; F (3,34) ϭ 15, p Ͻ 0.0001; one-way ANOVA).”
The paper relies on this without support.
Transient transfection of mCherry-C99 raises APP-βCTF levels without itself causing lysosomal defects independent of βCTF.
“transient transfection of a fluorescence-tagged CTF (mCherry-C99) significantly reduced in situ CTSD activity in 2N cells and further lowered CSTD activity in DS fibroblasts”
The paper relies on this without support.
Ts2 mice are a valid model of Down syndrome.
“neurons from Ts2 mice modeling DS”
“primary cortical neurons from Ts2 mice”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“despite a reduction in lysosomal activity [41]”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [41]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
“t (43) ϭ 2.562, p ϭ 0.014 for Lyso number”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Decreased lysosomal turnover of autophagic protein substrates in DS fibroblasts
“t (43) ϭ 2.562, p ϭ 0.0004 for Lyso size”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
“␥-secretase inhibitor L-685,485 (10 M) for 24 h”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Materials and Methods
“␥-secretase inhibitor (L-685,458; Tocris Bioscience)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > siAPP knockdown of APP expression in DS fibroblasts rescues lysosomal function
“Fig. 4G; t (10) ϭ 0.513, p ϭ 0.619 for APP”
§ Cellular/Molecular Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-CTF (C99) > Discussion
“F, mRNA level of APP, and lysosomal enzymes and (G) TFE3 and TFEB in 2N and DS fibroblasts”
Citations
Cites
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364
limma powers differential expression analyses for RNA-sequencing and microarray studies
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv007 · Cited by 40,458
Mapping and quantifying mammalian transcriptomes by RNA-Seq
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L., & Wold, B. (2008) · Nature Methods · doi:10.1038/nmeth.1226 · Cited by 13,696
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876 · cited 2×
“…of internalized cargoes and cell signaling, endosomes are major sites of APP processing by site cleaving enzyme 1 (BACE1), generating cleaved carboxy terminal fragment of APP ( CTF) (Vassar et al., 1999), which mediates AD-related endosome dysfunction and diverse neuronal deficits (Nixon, 2017).”
BackgroundImpairment of starvation-induced and constitutive autophagy in Atg7 -deficient mice
Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200412022 · Cited by 2,331
Kimura, S., Noda, T., & Yoshimori, T. (2007) · Autophagy · doi:10.4161/auto.4451 · Cited by 2,278 · cited 6×
“Inhibitors used were AZD8055 (Selleck Chemicals), leupeptin and Pepstatin A (Peptide Institute), -secretase inhibitor (L-685,458; Tocris Bioscience), and -secretase inhibitor IV (565788, Calbiochem). mRFP-eGFP-LC3 DNA construct was kindly provided by Dr. Tamotsu Yoshimori (Osaka University) (Kimura et al., 2007; Lee e…”
BackgroundMethodInfluentialThe role of autophagy in neurodegenerative disease
Nixon, R. A. (2013) · Nature Medicine · doi:10.1038/nm.3232 · Cited by 2,059
Self-citationImpaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D. (2004) · Science · doi:10.1126/science.1101738 · Cited by 2,024 · cited 1×
“The rates of total protein degradation at the indicated times were calculated as a percentage of total radiolabeled protein degraded to soluble amino acids as described previously (Auteri et al., 1983; Cuervo et al., 2004).”
MethodSelf-citation[41] Cathepsin B, cathepsin H, and cathepsin L
Barrett, A. J., & Kirschke, H. (1981) · Methods in Enzymology · doi:10.1016/s0076-6879(81)80043-2 · Cited by 1,698
Lysosomal acidification mechanisms
Mindell, J. A. (2012) · Annual Review of Physiology · doi:10.1146/annurev-physiol-012110-142317 · Cited by 1,258
Cited by
Sorted by citations
Lysosomes as dynamic regulators of cell and organismal homeostasis
Ballabio, A., & Bonifacino, J. S. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0185-4 · Cited by 1,469
Lee, J.-H., Yang, D.-S., Goulbourne, C. N., Im, E., Stavrides, P., Pensalfini, A., Chan, H., Bouchet-Marquis, C., Bleiwas, C., Berg, M. J., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01084-8 · Cited by 638
Self-citationMechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
Nixon, R. A., & Rubinsztein, D. C. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00757-5 · Cited by 435
Self-citationMarzia Perluigi, A., Domenico, F. D., & Butterfield, D. A. (2023) · Physiological Reviews · doi:10.1152/physrev.00030.2022 · Cited by 322
Vaillant-Beuchot, L., Mary, A., Pardossi-Piquard, R., Bourgeois, A., Lauritzen, I., Eysert, F., Kinoshita, P. F., Cazareth, J., Badot, C., Fragaki, K., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-020-02234-7 · Cited by 263
“Several studies show that the β-secretase-derived APPCTF is neurotoxic perse [38, 45, 58, 85].”
Background
Metadata
- Authors
- Jiang, Y., Sato, Y., Im, E., Berg, M., Bordi, M., Darji, S., Kumar, A., Mohan, P. S., Bandyopadhyay, U., Diaz, A., Cuervo, A. M., & Nixon, R. A.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- University of Rome Tor Vergata (IT)
- Albert Einstein College of Medicine (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2019-05-01
- Volume
- 39
- Issue
- 27
- Pages
- 5255-5268
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6607756
- OpenAlex
- W2943621977
- Cited by
- 166
- References
- 110
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 15 · 2023: 23 · 2022: 20 · 2021: 36 · 2020: 33 · 2019: 8
- FWCI
- 13.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institute on Aging (P01AG017617)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- Down syndrome, lysosomal dysfunction, lysosomal acidification, amyloid precursor protein, C99, BACE1, cathepsin D, autophagy, lysosomal enzymes, sporadic Alzheimer's disease, neurodegeneration
- MeSH terms
- Alzheimer Disease, Cells, Cultured, Down Syndrome, Fibroblasts, Humans, Lysosomes, Peptide Fragments, Amyloid beta-Protein Precursor, Proteolysis
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