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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Written from the paper’s full text.
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
The cited sources support only part of this claim — read each source’s verdict below.
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.
- 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.
- 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.
- 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.
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.
- 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.
- 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.
- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
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.
- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
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.
- 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.
- 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.
- 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 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.
- 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
“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.
- 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.
- 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.
- 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.
- 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
“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
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“…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
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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
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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
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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].”
BackgroundA gene toolbox for monitoring autophagy transcription
Bordi, M., De Cegli, R., Testa, B., Nixon, R. A., Ballabio, A., & Cecconi, F. (2021) · Cell Death & Disease · doi:10.1038/s41419-021-04121-9 · Cited by 131
“We earlier reported that DS fibroblasts exhibit a perturbation of lysosomal activities driven by APP-βCTF-dependent compromised luminal acidification [41]; interestingly, in these cells, among the “lysosomal biogenesis” genes, most of them (18) were not changed, while 7 were upregulated and 1 downregulated, CLCN7, whi…”
BackgroundSelf-citationPensalfini, A., Kim, S., Subbanna, S., Bleiwas, C., Goulbourne, C. N., Stavrides, P. H., Jiang, Y., Lee, J., Darji, S., Pawlik, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108420 · Cited by 134
Self-citationLo, C. H., & Zeng, J. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00362-0 · Cited by 117
“6 units in primary dermal fibroblasts with PS1 A246E mutation obtained from patients with FAD [59] and in fibroblasts from patients with Down syndrome [13], respectively.”
BackgroundInfluentialAutophagy–lysosomal-associated neuronal death in neurodegenerative disease
Nixon, R. A. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02799-7 · Cited by 126
“APP-βCTF binds selectively to the V0a1 subunit and inhibits this association [94], thus linking its elevation in the lysosomes of AD neurons to the early decline in acidification [102, 130] and extreme autolysosomal and lysosomal pathology [94, 102, 124, 126, 130, 163].”
InfluentialSelf-citationPomilio, C., Gorojod, R. M., Riudavets, M., Vinuesa, A., Presa, J., Gregosa, A., Bentivegna, M., Alaimo, A., Alcon, S. P., Sevlever, G., et al. (2020) · GeroScience · doi:10.1007/s11357-020-00161-9 · Cited by 109
Opportunities, barriers, and recommendations in Down syndrome research
Hendrix, J. A., Amon, A., Abbeduto, L., Agiovlasitis, S., Alsaied, T., Anderson, H. A., Bain, L. J., Baumer, N., Bhattacharyya, A., Bogunovic, D., et al. (2021) · Translational Science of Rare Diseases · doi:10.3233/trd-200090 · Cited by 117
Hung, C., Tuck, E., Stubbs, V., van der Lee, S. J., Aalfs, C., van Spaendonk, R., Scheltens, P., Hardy, J., Holstege, H., & Livesey, F. J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109259 · Cited by 98
Wu, J. J., Cai, A., Greenslade, J. E., Higgins, N. R., Fan, C., Le, N. T. T., Tatman, M., Whiteley, A. M., Prado, M. A., Dieriks, B. V., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1917371117 · Cited by 86
“The impairment in autophagosome acidification found in our studies is also noteworthy, as it adds to growing evidence of similar defects in acidification that have been found within the endosomal–lysosomal system of several neurodegenerative diseases, including Alzheimer’s disease and Down syndrome (53, 70, 71).”
ResultDown syndrome and Alzheimer's disease: common molecular traits beyond the amyloid precursor protein
Gómez, W., Morales, R., Maracaja‐Coutinho, V., Parra, V., & Nassif, M. (2020) · Aging · doi:10.18632/aging.102677 · Cited by 94
“Recent studies have shown that C99 exhibits neurotoxic effects independently of Aβ-monomers or oligomers in animal models of AD and fibroblasts from AD patients [23, 26, 27].”
BackgroundInfluentialMonaco, A., & Fraldi, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00037 · Cited by 91
C99 selectively accumulates in vulnerable neurons in Alzheimer's disease
Pulina, M. V., Hopkins, M., Haroutunian, V. H., Greengard, P., & Bustos, V. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.09.002 · Cited by 90
Tsatsanis, A., Wong, B. X. W., Gunn, A. P., Ayton, S., Bush, A. I., Devos, D., & Duce, J. A. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0762-0 · Cited by 87
Im, E., Jiang, Y., Stavrides, P. H., Darji, S., Erdjument-Bromage, H., Neubert, T. A., Choi, J. Y., Wegiel, J., Lee, J.-H., & Nixon, R. A. (2023) · Science Advances · doi:10.1126/sciadv.adg1925 · Cited by 80
“*Results from this study and our previous studies (see references in parentheses) N/A: not applicable Model system Human Mouse DS Ts2 5xFAD or Tg2576 fibroblast Cortical neuronal culture Cortical Neuron In situ Cortical Neuron In situ Lysosomal pH (5) (26) Lysosomal enzymatic activity ̄ (5) ̄ (5) N/A N/A Lysos…”
ResultSelf-citationExosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases
Mathews, P. M., & Levy, E. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01347 · Cited by 81
The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease
Balusu, S., & Strooper, B. D. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02747-5 · Cited by 76
“In AD, reduced expression of lysosomal proteins like Cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) and subcellular mis-localization are potentially reflecting a hampered lysosomal acidification in both neurons and glia [69, 77, 122].”
BackgroundJiang, Y., Alam, J. J., Gomperts, S. N., Maruff, P. T., Lemstra, A. W., Germann, U. A., Stavrides, P. H., Darji, S., Malampati, S., Peddy, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32944-3 · Cited by 65
Self-citationThe amyloid precursor protein: a converging point in Alzheimer’s disease
Delport, A., & Hewer, R. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02863-x · Cited by 66
“They connected this elevation to reduced lysosome acidity and decreased cathepsin D activity, coupled with diminished uptake rate and intra-lysosomal cargo accumulation [48].”
BackgroundInfluentialRimal, S., Li, Y., Vartak, R. S., Geng, J., Tantray, I., Li, S., Huh, S., Vogel, H. S., Glabe, C. G., Grinberg, L. T., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01268-6 · Cited by 60
Kim, S., Cho, Y.-S., Kim, Y., Park, J., Yoo, S., Gwak, J., Kim, Y., Gwon, Y., Kam, T., & Jung, Y. (2023) · Autophagy · doi:10.1080/15548627.2023.2181614 · Cited by 65
Hark, T. J., Rao, N. R., Castillon, C., Basta, T., Smukowski, S. N., Bao, H., Upadhyay, A., Bomba-Warczak, E. K., Nomura, T., O'Toole, E. T., et al. (2020) · Cell Systems · doi:10.1016/j.cels.2020.11.007 · Cited by 60
Modulating lysosomal pH: a molecular and nanoscale materials design perspective
Zeng, J., Shirihai, O. S., & Grinstaff, M. W. (2020) · JoLS Journal of Life Sciences · doi:10.36069/jols/20201204 · Cited by 65
Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
Checler, F., Afram, E., Pardossi‐Piquard, R., & Lauritzen, I. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100489 · Cited by 63
Targeting Aggrephagy for the Treatment of Alzheimer’s Disease
Malampati, S., Song, J., Tong, B. C., Nalluri, A., Yang, C., Wang, Z., Sreenivasmurthy, S. G., Zhu, Z., Liu, J., Su, C.-F., et al. (2020) · Cells · doi:10.3390/cells9020311 · Cited by 60
Saurat, N. G., Minotti, A. P., Rahman, M. T., Sikder, T., Zhang, C., Cornacchia, D., Jungverdorben, J., Ciceri, G., Betel, D., & Studer, L. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.06.001 · Cited by 60
Hwang, J., Estick, C., Ikonne, U. S., Butler, D., Pait, M. C., Elliott, L. H., Ruiz, S., Smith, K., Rentschler, K. M., Mundell, C. T., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184432 · Cited by 55
“It should be noted that APP-βCTF accumulation was implicated in lysosomal dysfunction independent of Aβ production [35,50], and that endosomal–lysosomal dysregulation was found in MCI independent of Aβ pathology [51].”
BackgroundAccumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer’s disease
Lee, S.-E., Kwon, D., Shin, N., Kong, D., Kim, N. G., Kim, H.-Y., Kim, M.-J., Choi, S. W., & Kang, K.-S. (2022) · Cell Death Discovery · doi:10.1038/s41420-021-00796-3 · Cited by 53
Tau is not necessary for amyloid-β–induced synaptic and memory impairments
Puzzo, D., Argyrousi, E. K., Staniszewski, A., Zhang, H., Calcagno, E., Zuccarello, E., Acquarone, E., Fà, M., Puma, D. D. L., Grassi, C., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137040 · Cited by 53
Pérez‐González, R., Kim, Y., Miller, C., Pacheco‐Quinto, J., Eckman, E. A., & Levy, E. (2020) · The FASEB Journal · doi:10.1096/fj.202000823r · Cited by 57
Alzheimer’s Disease: A Molecular View of β-Amyloid Induced Morbific Events
Asik, R. M., Suganthy, N., Aarifa, M. A., Kumar, A., Szigeti, K., Máthé, D., Gulyás, B. Z., Archunan, G., & Padmanabhan, P. (2021) · Biomedicines · doi:10.3390/biomedicines9091126 · Cited by 54
Self-citationLysosome-Mitochondrial Crosstalk in Cellular Stress and Disease
Kiraly, S., Stanley, J., & Eden, E. R. (2025) · Antioxidants · doi:10.3390/antiox14020125 · Cited by 58
Yang, J., Zhang, W., Zhang, S., Iyaswamy, A., Sun, J., Wang, J., & Yang, C. (2023) · Aging and Disease · doi:10.14336/ad.2022.0927 · Cited by 49
“Elevated β-CTF is involved in lysosomal pH elevation and aggregation of substrates, thus leading to dysfunction of lysosomes [42].”
BackgroundAyton, S., & Bush, A. I. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101212 · Cited by 45
Lauritzen, I., Bécot, A., Bourgeois, A., Pardossi‐Piquard, R., Biferi, M. G., Barkats, M., & Checler, F. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0176-6 · Cited by 50
Compromised autophagy and mitophagy in brain ageing and Alzheimer’s diseases.
Caponio, D., Veverová, K., Zhang, S.-Q., Shi, L., Wong, G., Vyhnalek, M., & Fang, E. F. (2022) · Aging Brain · doi:10.1016/j.nbas.2022.100056 · Cited by 45
Hung, C., Fertan, E., Livesey, F. J., Klenerman, D., & Patani, R. (2024) · Brain · doi:10.1093/brain/awae092 · Cited by 42
“Given the role of an extra APP gene copy in causing lysosomal acidification deficits in DS, 17 we hypothesized that APP ASOs may rescue cathepsin D activity by restoring normal lysosomal acidity.”
Sorting Out the Role of the Sortilin-Related Receptor 1 in Alzheimer’s Disease
Barthelson, K., Newman, M., & Lardelli, M. T. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-200177 · Cited by 43
“interestingly, also the PSEN1 holoprotein [127]) is required for acidification of the endo-lysosomal system [128].”
BackgroundBarthelson, K., Pederson, S., Newman, M., & Lardelli, M. T. (2020) · Molecular Brain · doi:10.1186/s13041-020-00681-7 · Cited by 39
Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules
Lanzillotta, C., & Domenico, F. D. (2021) · Biomolecules · doi:10.3390/biom11020266 · Cited by 36
“Nixon and colleagues found that a moderate increase in C99 levels was sufficient to impair lysosomal function in DS due to an increase in the luminal organelle pH [183].”
BackgroundAutophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration
Hussain, M. S., Agrawal, N., Ilma, B., Rekha, M. M., Nayak, P. P., Kaur, M., Khachi, A., Goyal, K., Rekha, A., Gupta, S., et al. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70503 · Cited by 35
“Lysosomal impairment has also been observed in connection with the APP- β-CTF in individuals with Down syndrome, which typically progresses to AD [266].”
Lu, B. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.970654 · Cited by 28
“C99) can cause toxicity in an Aβ-independent manner (Jiang et al., 2010; Lauritzen et al., 2012; Hung and Livesey, 2018; Jiang et al., 2019; Kwart et al., 2019).”
BackgroundIron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer’s Disease
Hin, N., Newman, M., Pederson, S., & Lardelli, M. T. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210200 · Cited by 28
“Recently Jiang et al. [105] showed that increased (cid”
Jaye, S., Sandau, U. S., & Saugstad, J. A. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1378576 · Cited by 26
Tosh, J. L., Rhymes, E. R., Mumford, P., Whittaker, H. T., Pulford, L. J., Noy, S. J., Cleverley, K., LonDownS Consortium, Strydom, A., Fisher, E., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-85062-3 · Cited by 26
Tramutola, A., Lanzillotta, S., Aceto, G., Pagnotta, S. E., Ruffolo, G., Cifelli, P., Marini, F., Ripoli, C., Palma, E., Grassi, C., et al. (2023) · Antioxidants · doi:10.3390/antiox12010111 · Cited by 27
“To clarify this aspect, we evaluated DYRK1A protein, a kinase involved in TAU phosphorylation [61,62] whose gene is triplicated in DS [63,64].”
Lin, H., Tang, M., Ji, C., Girardi, P., Cvetojevic, G., Chen, D., Koren, S. A., & Johnson, G. V. W. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.10.024 · Cited by 26
Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review
von Scheibler, E. N. M. M., van Eeghen, A. M., de Koning, T. J., Kuijf, M. L., Zinkstok, J., Müller, A. R., van Amelsvoort, T., & Boot, E. (2022) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.13577 · Cited by 26
Takasugi, N., Komai, M., Kaneshiro, N., Ikeda, A., Kamikubo, Y., & Uehara, T. (2023) · Cells · doi:10.3390/cells12030454 · Cited by 29
“Furthermore, similar lysosome defects occur in DS primary fibroblasts and show the dependency on C99 accumulation [112].”
BackgroundAn Alternative View of Familial Alzheimer’s Disease Genetics
Lardelli, M. T. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230313 · Cited by 24
“Indeed, the strongest genetic risk factor for sporadic (non-familial) AD, the (cid:5) 4 allele of APOE ( APOE4 ), reduces lysosomal acidification relative to the (cid:5) 3 allele [79] (in common with fAD mutations in APP [21] and the presenilins [80]).”
InfluentialFocusing on cellular biomarkers: The endo-lysosomal pathway in Down syndrome
Botté, A., & Potier, M. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.002 · Cited by 22
Oxidative Stress in Down and Williams-Beuren Syndromes: An Overview
Ferrari, M., & Stagi, S. (2021) · Molecules · doi:10.3390/molecules26113139 · Cited by 27
“Possible additional influences of other triplicated chromosome 21 genes or metabolic factors, such as oxidative stress, lipid peroxidation, and protein nitration, may be considered likely additive factors in corrupting lysosome functions [20,55].”
BackgroundCheng, F., Fransson, L., & Mani, K. (2020) · Glycobiology · doi:10.1093/glycob/cwaa011 · Cited by 21
Ledreux, A., Thomas, S., Hamlett, E. D., Trautman, C. W., Gilmore, A., Hager, E. R., Paredes, D., Margittai, M., Fortea, J., & Granholm, A. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10173931 · Cited by 23
Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches
Farrell, C., Mumford, P., & Wiseman, F. K. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.909669 · Cited by 22
Dong, Y., Newman, M., Pederson, S., Barthelson, K., Hin, N., & Lardelli, M. T. (2021) · BMC Genomics · doi:10.1186/s12864-021-07509-1 · Cited by 21
“affect acidification of the endolysosomal pathway [75] and so would be expected to affect cellular iron homeo-”
BackgroundMechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome
Chen, X., Xing, Z., Chen, Q.-D., Salvi, R., Zhang, X., Tycko, B., Mobley, W. C., & Yu, Y. E. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.700280 · Cited by 26
“In addition to disrupting early endosomes, β-CTF was also shown to mediate APP-induced dysfunction of the lysosomal system through affecting the expression and maturation and/or activity of lysosomal enzymes including cathepsin D, possibly through APP-induced abnormal lysosomal acidification in DS fibroblasts and the…”
BackgroundEndosome Dysregulation in Down Syndrome: A Potential Contributor to Alzheimer Disease Pathology
Filippone, A., & Praticò, D. (2021) · Annals of Neurology · doi:10.1002/ana.26042 · Cited by 20
“However, both parameters are altered in human DS fibroblasts and primary cortical neurons from Ts2 mice, reflecting an abnormal turnover of endocytic substrates (see Table).(45,51)”
BackgroundXu, H., Zhu, Y., Chen, X., Yang, T., Wang, X., Xu, S., Xie, X., Hu, M., Jiang, L., Cheng, J., et al. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03131-y · Cited by 20
Tang, M., Yarragudi, S. B., Pan, P., Yang, K., Kanamala, M., & Wu, Z. (2024) · Journal of Liposome Research · doi:10.1080/08982104.2024.2389969 · Cited by 19
“…drug delivery to cancer cells. however, it might affect the use of Psl in some diseases with dysfunctional lysosomes, such as alzheimer’s disease [45]. hence, these studies have demonstrated that the overall liposome uptake is size dependent and that the cellular uptake process is governed by…”
New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease
Venegas-Zamora, L., Bravo-Acuña, F., Sigcho, F., Gómez, W., Bustamante-Salazar, J., Pedrozo, Z., & Parra, V. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2021.792231 · Cited by 19
“Thus, the decreased lysosome activity related with an altered autophagy process observed primarily in DS neurons (Jiang et al., 2019) could suggest a diminished or altered mitophagy that could, in turn, explain the mitochondrial dysfunction and increased oxidative ROS production observed in DS…”
BackgroundInfluentialLeVine, S. M. (2024) · Cells · doi:10.3390/cells13080689 · Cited by 20
Lin, S., Leitao, A. D. G., Fang, S., Gu, Y., Barber, S., Gilliard-Telefoni, R., Castro, A., Sung, K., Shen, R., Florio, J. B., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106010 · Cited by 17
“This finding is consistent with previous studies demonstrating that β -CTFs of APP impair endosomal trafficking in an early phase of cellular pathogenesis in AD (Cataldo et al., 2003; Israel et al., 2012; Jiang et al., 2019; Kim et al., 2016; Xu et al., 2016).”
ResultGiuliano, S., Montemagno, C., Domdom, M. A., Teisseire, M., Brest, P., Klionsky, D. J., Hofman, P. M., Pagès, G., & Mograbi, B. (2023) · Autophagy · doi:10.1080/15548627.2023.2214960 · Cited by 17
“In this regard, the observation that the APP-derived fragment APP-βCTF that accumulates in the brains of sporadic AD patients similarly inhibits V-ATPase activity [46,52] is of particular interest.”
BackgroundCell models for Down syndrome-Alzheimer’s disease research
Wu, Y., West, N. R., Bhattacharyya, A., & Wiseman, F. K. (2022) · Neuronal Signaling · doi:10.1042/ns20210054 · Cited by 17
Wu, Y., Mumford, P., Noy, S., Cleverley, K., Mrzyglod, A., Luo, D., van Dalen, F., Verdoes, M., Fisher, E. M. C., & Wiseman, F. K. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01632-8 · Cited by 16
“These data 409 are consistent with a decrease in cathepsin D activity reported in DS patient fibroblasts 410 [19].”
BackgroundResultInfluentialA CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease
Shang, Y., Sun, X., Chen, X., Wang, Q., Wang, E. J., Miller, E., Xu, R., Pieper, A. A., & Qi, X. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02499-0 · Cited by 15
“While neurotoxic Aβ peptide produced via proteolysis of amyloid precursor protein (APP) is a major component of AD pathogenesis, other APP proteolytic fragments, such as C99 and amyloid precursor protein intracellular domain (AICD), also drive pathology [23, 26, 30, 50, 63].”
BackgroundMitochondrial dysfunction, cause or consequence in neurodegenerative diseases?
Acker, Z. P. V., Leroy, T., & Annaert, W. G. (2024) · BioEssays · doi:10.1002/bies.202400023 · Cited by 20
Martá-Ariza, M., Leitner, D. F., Kanshin, E., Suazo, J., Giusti Pedrosa, A., Thierry, M., Lee, E. B., Devinsky, O., Drummond, E., Fortea, J., et al. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02844-z · Cited by 15
Bécot, A., Pardossi‐Piquard, R., Bourgeois, A., Duplan, E., Xiao, Q., Diwan, A., Lee, J., Lauritzen, I., & Checler, F. (2020) · Cells · doi:10.3390/cells9051204 · Cited by 16
“Later on, it was shown that C99 accumulation also induces lysosomal-autophagic pathology in both cellular and animal AD models [5,6,8,10].”
BackgroundVesicular trafficking and cell-cell communication in neurodevelopment and neurodegeneration
Amin, S., & Taverna, E. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1600034 · Cited by 14
“…the extra copy of amyloid precursor gene (APP) on chromosome 21 leads to the accumulation of β-cleaved carboxy-terminal fragment of APP (APP-β-CTF or C99), in turn impairing of lysosomal acidification via the inhibition of v-ATPase (Jiang et al., 2019).”
Puente-Bedia, A., Berciano, M. T., Martínez‐Cué, C., Lafarga, M., & Rueda, N. (2022) · Antioxidants · doi:10.3390/antiox11122438 · Cited by 13
“has demonstrated that an early neuropathological manifestation in DS and AD is the dysfunction of endosomal protein sorting and trafficking, which ultimately leads to the impairment of lysosomal functions [32,83,84].”
BackgroundInfluentialEysert, F., Kinoshita, P. F., Lagarde, J., Lacas‐Gervais, S., Xicota, L., Dorothée, G., Bottlaender, M., Checler, F., Potier, M., Sarazin, M., et al. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01807-x · Cited by 14
“Accordingly, defects in general autophagy and lysosomal activity in AD have been associated with APP-CTFs accumulation [8–10].”
BackgroundYamamoto, K., Yamamoto, R., & Kato, N. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.660319 · Cited by 13
Barthelson, K., Newman, M., & Lardelli, M. T. (2021) · Disease Models & Mechanisms · doi:10.1242/dmm.049187 · Cited by 14
“This is not unexpected, as acidification of the endolysosomal system is impaired by increased levels of the β-CTF fragment of APP (also known as C99 and generated by β-secretase cleavage of APP (Jiang et al., 2019)).”
BackgroundInfluentialBarthelson, K., Dong, Y., Newman, M., & Lardelli, M. T. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210128 · Cited by 13
“The consequent increased expression of APP’s β545 CTF/C99 fragment (generated by β-secretase cleavage of AβPP without γ-secretase cleavage) 546 affects endolysosomal pathway acidification [97] in a similar manner to EOfAD mutations of 547 PSEN1 [98].”
BackgroundFructuoso, M., Vermeiren, Y., Boluda, S., Stimmer, L., Crans, R. A. J., Xicota, L., Eisel, U., Ortí-Casañ, N., Bun, P., Duyckaerts, C. J., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70262 · Cited by 14
Tang, Z., Peng, Y., Jiang, Y., Wang, L., Guo, M., Chen, Z., Luo, C., Zhang, T., Xiao, Y. C., Ni, R., et al. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150127 · Cited by 12
Self-citationJiang, H., Pederson, S., Newman, M., Dong, Y., Barthelson, K., & Lardelli, M. T. (2020) · PLoS ONE · doi:10.1371/journal.pone.0232559 · Cited by 13
Leyton, E., Matus, D., Espinoza, S., Benitez, J. M., Cortés, B. I., Gómez, W., Arévalo, N. B., Murgas, P., Manque, P., Woehlbier, U., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201264 · Cited by 11
“An incomplete autophagic flux due to impairment of the autophagosome fusion with the lysosome or reduced lysosomal activity is associated with neurodegeneration, especially in AD [11, 19, 28–32].”
InfluentialYoon, L., Botham, R. C., Verhelle, A., Wu, Y., Cole, C. M., Tan, E. P., Massey, L. A., Sanz-Martinez, P., Chou, C., Xu, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.29.509997 · Cited by 11
Cyanide overproduction impairs cellular bioenergetics in Down syndrome
Petrosino, M., Zuhra, K., Kieronska‐Rudek, A., et al. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00719 · Cited by 10
“Indeed, we have observed a markedly higher levels of the lysosomal marker LAMP-1 in DS fibroblasts compared to control (suggestive of lysosomal hypertrophy), and several prior reports demonstrate that DS lysosomes exhibit significant functional alterations in DS [13,14,26,27].”
Hutchison, J. M., Capone, R. F., Luu, D. D., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100940 · Cited by 10
“S15) (58).”
Gene therapy using Aβ variants for amyloid reduction
Park, K., Wood, C. A., Li, J., Taylor, B. C., Oh, S.-W., Young, N. L., & Jankowsky, J. L. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.02.026 · Cited by 11
Chen, X., Zuo, X., Becker, A., & Mobley, W. C. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70046 · Cited by 9
“Because lysosomal cathepsins B, L, and D are linked to AD, 47–49 we investigated their levels in the frontal cortex of individuals with DS-AD and DS. Cathepsins B and L showed significant increases in the absence of changes in their mRNAs (Figure S5A–”
Chen, X., Zuo, X., Becker, A., Mante, M., Florio, J. B., Jadhav, S. G., Albay, R., Johnstone, A. D., Karachentsev, D., Rissman, R. A., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70022 · Cited by 9
Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s diseasePreprint
Hin, N., Newman, M., Pederson, S., & Lardelli, M. T. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.01.071498 · Cited by 9
“The observations of Nixon and colleagues that acidification of the endolysomal pathway is affected both by fAD mutations in PSEN1 [46] and excessive dosage of the APP gene [54], together with our observations from our fAD-like psen1Q96_K97del/+ mutant zebrafish, support the possibility that fAD brains may suffer a fer…”
ResultNeuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease
Espinoza, S., Grünenwald, F., Gómez, W., García, F., Abarzúa-Catalán, L., Oyarce-Pezoa, S., Hernandez, M. F., Cortés, B. I., Uhrig, M., Ponce, D. P., et al. (2022) · Cells · doi:10.3390/cells11121860 · Cited by 8
Lardelli, M. T., Baer, L., Hin, N., Allen, A. G., Pederson, S., & Barthelson, K. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230522 · Cited by 9
“Insufficient lysosomal acidification is also an effect-in-common of EOfAD mutations in APP [45] and PSEN1 [46], as well as due to the (cid:4) 4 allele of APOE [47] and so would be expected to disturb cellular iron homeostasis.”
Zoltowska, K. M., Das, U., Lismont, S., Enzlein, T., Maesako, M., Houser, M. C., Franco, M. L., Özcan, B., Moreira, D. G., Karachentsev, D., et al. (2023) · eLife · doi:10.7554/elife.90690 · Cited by 14
LeVine, S. M. (2023) · Cells · doi:10.3390/cells12222641 · Cited by 10
“In sporadic Alzheimer’s disease, the increased risk ε 4 allele of APOE is thought to elevate the pH of lysosomes within astrocytes [172], and in Down’s syndrome the proteolytically cleaved carboxy fragment of the amyloid β precursor protein causes an elevated lysosomal pH [173,174].”
BackgroundAssociation of Retromer Deficiency and Tau Pathology in Down Syndrome
Curtis, M. E., Smith, T., Yu, D., & Praticò, D. (2022) · Annals of Neurology · doi:10.1002/ana.26321 · Cited by 8
Ketamine promotes the amyloidogenic pathway by regulating endosomal pH
Ren, W., Lou, H., Ren, X., Wen, G., Wu, X., Xia, X., Wang, S., Yu, X., Yan, L., Zhang, G., et al. (2022) · Toxicology · doi:10.1016/j.tox.2022.153163 · Cited by 8
Rosa, L. D., Fasano, D., Zerillo, L., Valente, V., Izzo, A., Mollo, N., Amodio, G., Polishchuk, E., Polishchuk, R., Melone, M. A. B., et al. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.867989 · Cited by 7
“In addition, some findings have provided evidence that the rise of APP-βCTF (the β-cleaved carboxyl terminal fragment), consequent to APP triplication, leads to lysosomal dysfunction (Colacurcio et al., 2018; Jiang et al., 2019).”
BackgroundThe Azalea Hypothesis of Alzheimer Disease: A Functional Iron Deficiency Promotes Neurodegeneration
LeVine, S. M. (2023) · The Neuroscientist · doi:10.1177/10738584231191743 · Cited by 8
“This fragment has been shown to impair lysosomal function, resulting in an increase in lysosomal pH (Delport and Hewer 2022; Jiang and others 2019).”
Urinary Proteomics for Noninvasive Prenatal Screening of Trisomy 21: New Biomarker Candidates
Gao, L., Zhang, J., Ran, X., Xue, J., Xing, Y., Dai, T., Song, W., Wu, Z., Sun, W., & Shan, D. (2021) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2021.0154 · Cited by 7
“TIMP2 is involved in very early local maternal recognition of pregnancy by acting on matrix metallopeptidases (Ulbrich et al., 2011), while LAMP2 is required for lysosome-mediated degradative systems and lysosomal dysfunction has been found in trisomy 21 (Jiang et al., 2019).”
Wang, Z., Zhang, K., Huang, M., Shang, D., He, X., Wu, Z., Xu, Y., & Zhang, X. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.04.019 · Cited by 6
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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