The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index; 11 of the 22 sources its claims cite were checked for support.
App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome
Open accessAbstract
Altered neuronal endocytosis is the earliest known pathology in sporadic Alzheimer's disease (AD) and Down syndrome (DS) brain and has been linked to increased Aβ production. Here, we show that a genetic model of DS (trisomy 21), the segmental trisomy 16 mouse Ts65Dn, develops enlarged neuronal early endosomes, increased immunoreactivity for markers of endosome fusion (rab5, early endosomal antigen 1, and rabaptin5), and endosome recycling (rab4) similar to those in AD and DS individuals. These abnormalities are most prominent in neurons of the basal forebrain, which later develop aging-related atrophy and degenerative changes, as in AD and DS. We also show that App, one of the triplicated genes in Ts65Dn mice and human DS, is critical to the development of these endocytic abnormalities. Selectively deleting one copy of App or a small portion of the chromosome 16 segment containing App from Ts65Dn mice eliminated the endosomal phenotype. Overexpressing App at high levels in mice did not alter early endosomes, implying that one or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype. These results identify an essential role for App gene triplication in causing AD-related endosomal abnormalities and further establish the pathogenic significance of endosomal dysfunction in AD.
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TL;DR
In the Ts65Dn segmental trisomy 16 mouse model of Down syndrome, triplication of App is necessary for AD-like neuronal early endosomal abnormalities, but not sufficient because APP overexpression alone did not reproduce them. The findings support endosomal dysfunction as an early pathogenic event relevant to Alzheimer’s disease and Down syndrome.
Key findings
- Ts65Dn mice developed enlarged rab5-positive early endosomes and increased immunoreactivity for endosome fusion markers rab5, rabaptin5, and EEA1, plus recycling marker rab4, most prominently in basal forebrain neurons; abnormalities appeared as early as 2 months and increased in number of affected neurons with age.
- Western blot analysis showed a 2.5-fold increase in rab4 levels in Ts65Dn mouse brains compared with 2N controls (p < 0.0006; n = 4).
- Removing one copy of App in Ts65Dn-App+/+/− mice or using Ts1Cje mice lacking the App-to-Sod1 trisomic segment eliminated the endosomal phenotype in MSN, NBM, neocortex, and hippocampus, with rab4 levels similar to controls.
- Transgenic mice overexpressing mutant human APP—twofold Swedish plus London mutations or sevenfold Swedish mutation—had normal-appearing rab5-positive early endosomes and normal patterns of EEA1, rab4, and rabaptin5, implying one or more additional genes on the triplicated MMU16 segment are required.
Methods
- Used segmental trisomy mice: Ts65Dn (n = 6), Ts1Cje (n = 4), and Ts65Dn-App+/+/− (n = 6), plus transgenic APP mice expressing Swedish (n = 6) or Swedish plus London mutations, and APP plus presenilin 1 mice (n = 6); controls were age-matched 2N littermates.
- Brain tissue from medial septal nucleus, nucleus basalis magnocellularis, hippocampus, neocortex, basal ganglia, and cerebellum was examined by immunocytochemistry for rab5, rab4, rabaptin5, and EEA1; Western blotting was used for rab4; thioflavin S was used to detect β-amyloid deposition.
- Aging effects were assessed in Ts65Dn and 2N controls at 6, 12, and 18 months of age.
Limitations
- The paper does not state a limitations section. Evident from the text: group sizes were small (n = 4–6 per group), and much of the endosomal assessment was qualitative immunocytochemistry, with only rab4 quantified by Western blot.
- The paper states that Ts65Dn mice do not deposit β-amyloid and, even at 24 months, do not exhibit extracellular β-amyloid plaques or neurofibrillary tangles, so late-stage AD pathology is not modeled.
- The paper states that increased App dosage is necessary but not sufficient for the endosomal phenotype and that one or more additional genes on the trisomic segment are required; candidate genes such as Sod1, BACE2, S100β, and ApoE are discussed but not experimentally tested here.
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Claims the paper makes
18 Own result · 10 Own interpretation · 4 Supported · 4 Partly supported · 3 No full text of the sources · 2 Supported so far · 1 Sources not found · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These same populations of basal forebrain neurons typically develop less severe atrophy in the Ts1Cje (Sago et al., 1998) and Ts65Dn-App ϩ/ϩ/Ϫ mice (our unpublished observation) or older ages compared with that occurring in age-matched Ts65Dn mice.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
What the sources say
- Partly supportedcites Sago et al., 1998 sourceExperimental — accuracy not yet measured
The Discussion reports that at six months, basal forebrain cholinergic neurons were normal in number and size in Ts1Cje mice, unlike the loss and size decrease seen in Ts65Dn mice. This supports the comparison for Ts1Cje at that age, but the paper does not establish that Ts1Cje neurons develop atrophy or address the comparison at older ages. The sentence attributes the Ts65Dn-App observation to unpublished work, not to Sago et al. (LLM, conf=0.82)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- 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
“Unlike what occurs in human disorders, however, Ts65Dn mice do not deposit -amyloid.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Introduction
What the sources say
- Supportedcites Holtzman et al., 1996 source
The Discussion states that App overexpression did not lead to Aβ deposition over the two-year lifespan of Ts65Dn mice. The Results also report no plaque-like abnormal staining in mice examined at 6 and 20 months. (LLM, conf=0.94)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Early endosomal alterations are the earliest known pathology in sporadic AD (SAD) and Down syndrome (DS), appearing in DS before birth, and in SAD, developing before -amyloid is deposited and as soluble A peptide levels first rise.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Introduction
What the sources say
- Partly supportedcites Cataldo et al., 1997 sourceExperimental — accuracy not yet measured
The paper’s opening summary reports early endosomal alterations in Alzheimer brains and says they were detectable at early stages of disease. It does not establish that they are the earliest known pathology, and its Tissue section describes AD cases and controls, not Down syndrome cases. The claim about Down syndrome is therefore unsupported by this source. (LLM, conf=0.88)
- Not matchedcites Cataldo et al., 2000a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites Cataldo et al., 2001 source
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Endosomal alterations in AD and DS develop in otherwise normal-appearing neurons of regions that become the most severely affected in the disease (Cataldo et al., 1997(Cataldo et al., , 2000a)), including hippocampus, neocortex, and basal forebrain.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Introduction
What the sources say
- Partly supportedcites Cataldo et al., 1997 sourceExperimental — accuracy not yet measured
The section “Early endosomes in neurons of AD brain are abnormally large” reports enlarged endosomes in at-risk neocortical neurons in AD, and the Morphometric analysis section says the neurons examined were intact (page numbers unavailable). This supports the AD neocortex portion, but this paper does not establish the claim for Down syndrome, hippocampus, or basal forebrain, or show when the alterations develop relative to other disease changes. (LLM, conf=0.88)
- Not matchedcites Cataldo et al., 2000a
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: passes — 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
“Ts65Dn mice also exhibit age-related atrophy and neurodegeneration of basal forebrain cholinergic neurons (BFCNs) and extensive astrocytic hypertrophy resembling these aspects of the neuropathology in AD and DS (Holtzman et al., 1996;Cooper et al., 2001).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Introduction
What the sources say
- Supportedcites Holtzman et al., 1996 source
The Discussion reports that atrophy and progressive loss of basal forebrain cholinergic neurons appeared in adult Ts65Dn mice, not during development, and compares this age-related degeneration with DS. The Results describe atrophy of the remaining neurons as analogous to that seen in AD. (LLM, conf=0.93)
- Supportedcites Cooper et al., 2001 source
The Discussion reports age-related regression of basal forebrain cholinergic neurons in Ts65Dn mice, including decreased cell size and number between 6 and 12 months. The Abstract identifies these changes as paralleling aspects of AD and DS. The paper describes the reduced neuron count as apparent loss, not proof that the cells died. (LLM, conf=0.91)
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
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
“Ts1Cje and TsDn65-App ϩ/ϩ/Ϫ mice, which have two copies of App, showed normal endosomal morphology in the basal forebrain in contrast to Ts65Dn mice.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rab4 immunoreactivity was principally associated with small vesicular profiles consistent with the size and location of recycling vesicles.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > AD-like early endosomal abnormalities in neurons of Ts65Dn mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rab5 immu-nocytochemistry showed that neurons of both of these mouse strains displayed early endosomes of normal size in the MSN, NBM, neocortex, and hippocampus in numbers qualitatively similar to that seen in neurons of 2N brains (Fig. 4).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > App gene dosage modulates early endosomal morphology in Ts65Dn mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“A compensatory rise in levels of the GTPase rab4, which stimulates endosome recycling to the plasmalemma, was also detected in the same neuronal groups.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Immunocytochemistry showed that by 6 months of age, swollen, rab5-positive endosomes were present in most basal forebrain neurons of the MSN as well as the NBM.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > AD-like early endosomal abnormalities in neurons of Ts65Dn mice
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. 11
- Probably not a substantial claim. 3
- The quote only partly states this claim. 2
Every source the paper cites for this claim was checked and supports it.
In the paper
“These mice do not develop BFCN atrophy and degeneration, and they have less severe learning and behavioral deficits than Ts65Dn mice (Sago et al., 1998).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Introduction
What the sources say
- Supportedcites Sago et al., 1998 source
The Discussion reports that Ts1Cje mice had normal BFCN number and size at six months, unlike Ts65Dn mice, and describes Ts1Cje as less severely impaired. It also contrasts their learning and locomotor abnormalities. The findings are based on the ages and tests studied, rather than a lifetime assessment of degeneration. (LLM, conf=0.88)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Endosomal abnormalities, which are influenced by ApoE genotype (Cataldo et al., 1997), do not develop in familial AD caused by presenilin mutations (Cataldo et al., 2001), underscoring that they are AD subtype-specific and are also not a response to amyloid deposition.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Introduction
What the sources say
- Partly supportedcites Cataldo et al., 1997 sourceExperimental — accuracy not yet measured
The paper reports enlarged early endosomes in AD (section “Early endosomes in neurons of AD brain are abnormally large”) and discusses differences between ApoE isoforms in the endocytic pathway (section “Implications for β-amyloidogenesis and pathogenesis in AD”). It does not show that ApoE genotype influences the endosomal abnormalities themselves. The presenilin-mutation clause is attributed to Cataldo et al. (2001), not to this source. (LLM, conf=0.78)
- Not checked — no full text of the sourcecites Cataldo et al., 2001 source
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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A twofold overexpression of the combined Swedish and London mutations of APP and a sevenfold overexpression of the Swedish mutation of APP in these transgenic mice have been demonstrated previously (Sturchler-Pierrat et al., 1997).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > App gene dosage modulates early endosomal morphology in Ts65Dn mice
What the sources say
- Supportedcites Sturchler-Pierrat et al., 1997 source
The Results section (“APP Overexpression in Brains of Transgenic Mouse Lines”) identifies APP 22 as carrying the combined Swedish and London mutations and reports twofold expression relative to endogenous APP. It identifies APP 23 as carrying the Swedish mutation alone and reports sevenfold overexpression; Western blotting confirmed the degree of overexpression. (LLM, conf=0.94)
boosted- 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.
- Supported
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
“Finally, the ApoE gene, which is associated with increased risk of AD (Corder et al., 1993), is not located on the triplicated segment of MMU16, but it is overexpressed to higher levels in Ts65Dn mice than is predicted on the basis of gene dosage (Holtzman et al., 1996).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
What the sources say
- Not checked — no full text of the sourcecites Corder et al., 1993 source
- Supportedcites Holtzman et al., 1996 source
The Results identify ApoE as located on MMU-7, outside the triplicated MMU-16 segment, and report that its brain mRNA level was 1.5-fold higher in Ts65Dn mice than in controls. The Discussion explicitly says apoE was overexpressed more than predicted by gene dose. The AD-risk statement is separately attributed to Corder et al. in the citing sentence. (LLM, conf=0.94)
plaincorrelational- 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.
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
“Two segmental trisomy mouse models of DS, Ts65Dn (Davisson et al., 1990), and Ts1Cje (Sago et al., 1998) mice, survive to adulthood and exhibit a number of the morphological, biochemical, and transcriptional changes seen in the human disease (Davisson et al., 1990;Reeves et al., 1995;Holtzman et al., 1996).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Introduction
What the sources say
- Not checked — no full text of the sourcecites Davisson et al., 1990
- Supportedcites Sago et al., 1998 source
Sago et al. identify Ts1Cje as a partial trisomy 16 mouse model for Down syndrome, which is the identification supported by the citation attached to its name. The Results also report that Ts1Cje mice survived more than one year. The sentence cites other works for the broader claim about morphological, biochemical, and transcriptional changes. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites Reeves et al., 1995 source
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.
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It may state two separate claims as one.
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
“Not all neuronal populations in the Ts65Dn mice exhibited enlarged endosomes; neurons in the caudate nucleus and putamen (Fig. 3) or in cerebellar Purkinje cells displayed normal-sized early endosomes.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > AD-like early endosomal abnormalities in neurons of Ts65Dn mice
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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the levels of rabaptin5 and EEA1 immunoreactivities were higher in Ts65Dn mice than in age-matched littermate controls (Fig. 2).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > AD-like early endosomal abnormalities in neurons of Ts65Dn mice
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.
The quote only partly states this claim.
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
“Selectively deleting one copy of App or a small portion of the chromosome 16 segment containing App from Ts65Dn mice eliminated the endosomal phenotype.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The numbers of neurons in these regions containing abnormally large endosomes increased in Ts65Dn mice 12 months of age and older, although the magnitude of enlargement did not appear to differ from that seen in the young, 2-month-old mice.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > AD-like early endosomal abnormalities in neurons of Ts65Dn mice
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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 young Ts65Dn mice, these enlarged endosomes were prominent in a majority of the neurons in the MSN of the basal forebrain.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > AD-like early endosomal abnormalities in neurons of Ts65Dn mice
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.
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The quote only partly states this claim.
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
“These findings are consistent with observations that endosomal abnormalities in DS develop in some neurons before birth, which links this phenomenon with dosage of particular genes on the triplicated segment of chromosome 21.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Immunocytochemical studies of brain tissue from DS subjects have shown a direct correlation between the appearance of elevated levels of BACE-2 in brain and the presence of AD-like neuropathology (Motonaga et al., 2002).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
What the sources say
- Not checked — no full text of the sourcecites Motonaga et al., 2002 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.
In the paper
“It is relevant, in this regard, that another major genetic risk factor for AD, the ApoE4 allele, also accelerates the onset of endosome pathology in AD (Corder et al., 1993).”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
What the sources say
- Not checked — no full text of the sourcecites Corder et al., 1993 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.
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
“underscoring that they are AD subtype-specific and are also not a response to amyloid deposition.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > 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: 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
“Although increased App gene dosage is necessary for endosome pathology to develop in Ts65Dn mice, it is not sufficient, because overexpressing APP alone did not cause endosome pathology or atrophy of basal forebrain neurons.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > 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.
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876 · cited 2×
“The importance of the endocytic pathway to Alzheimer’s disease (AD) pathogenesis is amply evidenced by its critical role in the processing and function of various proteins relevant to AD, including amyloid precursor protein (APP), amyloid (A ) peptide, apolipoprotein E (ApoE), low-density lipoprotein, and low-density…”
Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease.
Griffin, W. S., Stanley, L. C., Ling, C., White, L., MacLeod, V, Perrot, L. J., White, C. L., & Araoz, C. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.19.7611 · Cited by 1,777
Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.-H., Mistl, C., Rothacher, S., Ledermann, B., Bürki, K., Frey, P., Paganetti, P. A., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.24.13287 · Cited by 1,507
Self-citationThe small GTPase rab5 functions as a regulatory factor in the early endocytic pathway
Bucci, C., Parton, R. G., Mather, I. H., Stunnenberg, H. G., Simons, K., Hoflack, B., & Zerial, M. (1992) · Cell · doi:10.1016/0092-8674(92)90306-w · Cited by 1,398
Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., et al. (1998) · Nature Medicine · doi:10.1038/nm0198-097 · Cited by 1,386
A mouse model for Down syndrome exhibits learning and behaviour deficits
Reeves, R. H., Irving, N. G., Moran, T. H., Wohn, A., Kitt, C., Sisodia, S. S., Schmidt, C., Bronson, R. T., & Davisson, M. T. (1995) · Nature Genetics · doi:10.1038/ng1095-177 · Cited by 913
Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gomez-Isla, T., Hyman, B. T., & Nixon, R. A. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64538-5 · Cited by 776
Self-citationApoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro
Busciglio, J., & Yankner, B. A. (1995) · Nature · doi:10.1038/378776a0 · Cited by 741
β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity
Zheng, H., Jiang, M., Trumbauer, M. E., SIRINATHSINGHJI, D. J. S., Hopkins, R., Smith, D. W., HEAVENS, R. P., Dawson, G. R., Boyce, S., Conner, M. W., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90073-x · Cited by 699
Research works printed but not linked: 3
- 1990, Prog Clin Biol Res, 360, 263
- 2002, Neurobiol Aging, 23, 50
- 1998, Nat Med, 1, 97
Cited by
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Items 101–200 of 241
Ren, R., Zhang, Y., Dammer, E. B., Zhou, Y., Wang, L., Liu, X., Feng, B.-L., Jiang, G., Chen, S., Wang, G., et al. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9484-8 · Cited by 45
Bretou, M., Sannerud, R., Escamilla‐Ayala, A., Leroy, T., Vrancx, C., Acker, Z. P. V., Perdok, A., Vermeire, W., Vorsters, I., Keymolen, S. V., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.03.030 · Cited by 47
Costa, A. C. S. (2011) · Developmental Neuroscience · doi:10.1159/000330861 · Cited by 44
Kelley, C. M., Ash, J. A., Powers, B. E., Velázquez, R., Alldred, M. J., Ikonomović, M. D., Ginsberg, S. D., Strupp, B. J., & Mufson, E. J. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666150921100515 · Cited by 40
Function and inhibition of DYRK1A: Emerging roles of treating multiple human diseases
Yang, Y., Fan, X., Liu, Y., Ye, D., Liu, C., Yang, H., Su, Z., Zhang, Y., & Liu, Y. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115521 · Cited by 43
Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome
Andrade‐Talavera, Y., Benito, I., Casañas, J. J., Moreno, A. R., & Montesinos, M. L. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.09.005 · Cited by 42
“Very interestingly, it has been recently reported that cortical synaptosomes from the DS model Ts65Dn also fail to induce further activation of the TrkB signaling pathway when exposed to BDNF (Nosheny et al., 2015).”
Dissecting Alzheimer disease in Down syndrome using mouse models
Choong, X. Y., Tosh, J., Pulford, L. J., & Fisher, E. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00268 · Cited by 41
Hung, C., Fertan, E., Livesey, F. J., Klenerman, D., & Patani, R. (2024) · Brain · doi:10.1093/brain/awae092 · Cited by 42
Alldred, M. J., Lee, S. H., Petkova, E., & Ginsberg, S. D. (2014) · Brain Structure and Function · doi:10.1007/s00429-014-0839-0 · Cited by 41
“While there has been linkage of some triplicated genes to AD pathogenesis, including amyloid-beta protein precursor (APP; Cataldo et al. 2003; Salehi et al. 2006), the genetic underpinnings and mechanism of this early onset AD pathology remain unclear.”
Gautier, M. K., & Ginsberg, S. D. (2020) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2020.109038 · Cited by 41
“…and DS patients (Perez et al., 2015; Colacurcio et al., 2018), in human DS fibroblasts (Cataldo et al., 2008), and in trisomic Ts2 and Ts65Dn mice (Cataldo et al., 2003; Jiang et al., 2016), two well-characterized murine models of DS. Importantly, the appearance of enlarged early endosomes often…”
BackgroundWeissmiller, A. M., Natera-Naranjo, O., Reyna, S. M., Pearn, M. L., Zhao, X., Nguyen, P. A. H., Cheng, S., Goldstein, L. S. B., Tanzi, R. E., Wagner, S. L., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118379 · Cited by 37
Barthelson, K., Pederson, S., Newman, M., & Lardelli, M. T. (2020) · Molecular Brain · doi:10.1186/s13041-020-00681-7 · Cited by 39
Neuroinflammatory Cytokines - The Common Thread in Alzheimer Pathogenesis
Griffin, W. S. T., Barger, S. W., & Chairman, D. P. A. V. (2011) · European Neurological Review · doi:10.17925/enr.2011.06.02.89 · Cited by 39
Endosomal dysfunction impacts extracellular vesicle release: Central role in Aβ pathology
Arbo, B. D., Cechinel, L. R., Palazzo, R. P., & Siqueira, I. R. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.101006 · Cited by 40
Duchon, A., Pothion, S., Brault, V., Sharp, A. J., Tybulewicz, V. L. J., Fisher, E., & Hérault, Y. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.10.023 · Cited by 45
“Region in the appearance of the craniofacial phenotype in another DS mouse model, the Ts65Dn mouse [39], or the contribution of single gene [5].”
Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome
Botté, A., Lainé, J., Xicota, L., Heiligenstein, X., Fontaine, G., Kasri, A., Rivals, I., Goh, P. A., Faklaris, O., Cossec, J., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00956-z · Cited by 35
Choi, J. H. K., Kaur, G., Mazzella, M. J., Morales‐Corraliza, J., Levy, E., & Mathews, P. M. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-122143 · Cited by 41
“In the DS mouse model Ts65Dn, neuronal early endocytic morphological disruption is dependent upon App gene triplication, arguing that increased AβPP expression is necessary for early endosomal disruption in the context of DS trisomy [6].”
InfluentialsAPP Enhances the Transdifferentiation of Adult Bone Marrow Progenitor Cells to Neuronal Phenotypes
Chen, C.-W. D., Boiteau, R. M., Lai, W., Barger, S. W., & Cataldo, A. M. (2006) · Current Alzheimer Research · doi:10.2174/156720506775697205 · Cited by 36
“Immunocytochemical studies were performed as previously described [25] on 40μm vibratome coronal sections of aldehydes-fixed tissue of transgenic and nontransgenic mouse brains.”
MethodSelf-citationAlldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., & Ginsberg, S. D. (2018) · Hippocampus · doi:10.1002/hipo.22832 · Cited by 35
“The well-established segmental trisomy Ts65Dn mouse model closely replicates human DS neuropathology (Cataldo et al., 2003; Davisson et al., 1993; Granholm, Sanders, & Crnic, 2000; Holtzman et al., 1996; Salehi et al., 2006; Seo & Isacson, 2005).”
BackgroundAlldred, M. J., Penikalapati, S. C., Lee, S. H., Heguy, A., Roussos, P., & Ginsberg, S. D. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02453-3 · Cited by 38
“BFCN changes begin approximately at 6 months of age (MO) [21, 31, 32, 41].”
BackgroundChapter 6 Monitoring Autophagy in Alzheimer's Disease and Related Neurodegenerative Diseases
Yang, D., Lee, J., & Nixon, R. A. (2009) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)04006-8 · Cited by 33
Self-citationThe in vivo Down syndrome genomic library in mouse
Hérault, Y., Duchon, A., Velot, É., Maréchal, D., & Brault, V. (2012) · Progress in brain research · doi:10.1016/b978-0-444-54299-1.00009-1 · Cited by 36
Critical genes in a critical region
Epstein, C. J. (2006) · Nature · doi:10.1038/441582a · Cited by 33
Self-citationAging and intellectual disability: Insights from mouse models of down syndrome
Ruparelia, A., Pearn, M. L., & Mobley, W. C. (2013) · Developmental Disabilities Research Reviews · doi:10.1002/ddrr.1127 · Cited by 37
“Ts1Cje mice, which lack the trisomic segment containing the App gene, do not show enlarged early endosomes [Cataldo et al., 2003].”
BackgroundInfluentialMechanisms of Neural and Behavioral Dysfunction in Alzheimer’s Disease
Wesson, D. W., Nixon, R. A., Levy, E., & Wilson, D. A. (2011) · Molecular Neurobiology · doi:10.1007/s12035-011-8177-1 · Cited by 34
“Further evidence links these endocytic pathway alterations to upstream dependence on APP and βCTF and to downstream consequences on neurotrophin signaling and cholinergic nerodegeneration [32, 58, 59].”
BackgroundSelf-citationD’Acunzo, P., Hargash, T., Pawlik, M., Goulbourne, C. N., Pérez‐González, R., & Levy, E. (2019) · Developmental Neurobiology · doi:10.1002/dneu.22708 · Cited by 32
“It was shown that APP‐CTFs‐derived endosomal dysfunctions are early and crucial neuropathological hallmarks of both AD and DS (Cataldo et al., 2003; Jiang et al., 2016; Kim et al., 2016).”
BackgroundChen, M., Wang, M., Wang, Q., Neff, R. A., Wang, E., Shen, Q., Reddy, J. S., Wang, X., Allen, M., Ertekin‐Taner, N., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12507 · Cited by 33
New Perspectives for the Rescue of Cognitive Disability in Down Syndrome
Bartesaghi, R., Haydar, T. F., Delabar, J. M., Dierssen, M., Martínez‐Cué, C., & Bianchi, D. W. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2775-15.2015 · Cited by 32
Mouse-based genetic modeling and analysis of Down syndrome
Xing, Z., Li, Y., Pao, A., Bennett, A. S., Tycko, B., Mobley, W. C., & Yu, Y. E. (2016) · British Medical Bulletin · doi:10.1093/bmb/ldw040 · Cited by 32
“Evidence has shown that the triplication of the App ortholog is required for mutant mice to exhibit enlargement of endosomes and impaired neurotrophin transport.(43,44) Together, these findings suggest that neuronal degeneration relevant to AD in DS is recapitulated in mutant mice.”
BackgroundKelley, C. M., Ginsberg, S. D., Alldred, M. J., Strupp, B. J., & Mufson, E. J. (2019) · Developmental Neurobiology · doi:10.1002/dneu.22700 · Cited by 29
“…of BFCNs, as well as possible treatment paradigms (Holtzman et al., 1996; Granholm et al., 2000; Cooper et al., 2001; Berger‐Sweeney, 2003; Cataldo et al., 2003; Hunter et al., 2003; Seo and Isacson, 2005; Contestabile et al., 2006; Moon et al., 2010; Ash et al., 2014; Kelley et al.,…”
BackgroundTranslational validity and implications of pharmacotherapies in preclinical models of Down syndrome
Rueda, N., Flórez, J., Dierssen, M., & Martínez‐Cué, C. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.001 · Cited by 30
Kleschevnikov, A. M., Belichenko, P. V., Salehi, A., & Wu, C. (2012) · Progress in brain research · doi:10.1016/b978-0-444-54299-1.00010-8 · Cited by 30
“Nixon and colleagues observed enlarged early endosomes and increased immunoreactivity for markers of early endosomes (Rab5, early endosomal antigen 1, and Rabaptin5) most prominently in neurons of the basal forebrain in Ts65Dn mice (Cataldo et al., 2003).”
BackgroundMethodGuix, F. X. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24526 · Cited by 30
“…are also present in a segmental trisomy 16 mouse model of DS with impaired nerve growth factor (NGF) axonal transport, similar to the findings in APP‐overexpressing cultured rat basal forebrain cholinergic neurons (Cataldo et al., 2003; Cattaneo & Calissano, 2012; Salehi et al., 2006).”
ResultLisgaras, C. P., & Scharfman, H. E. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106294 · Cited by 26
Amritraj, A., Hawkes, C. A., Phinney, A. L., Mount, H. T. J., Scott, C. D., Westaway, D. A., & Kar, S. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.05.004 · Cited by 26
Alterations of brain circuits in Down syndrome murine models
Gotti, S., Caricati, E., & Panzica, G. (2011) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2011.09.002 · Cited by 25
Tate, B. A., & Mathews, P. M. (2006) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2006.10.re2 · Cited by 48
Dosage of amyloid precursor protein affects axonal contact guidance in Down syndrome
Sosa, L. J., Postma, N. L., Estrada‐Bernal, A., Hanna, M., Guo, R., Busciglio, J. A., & Pfenninger, K. H. (2013) · The FASEB Journal · doi:10.1096/fj.13-232686 · Cited by 26
Ramireddy, S., Sajeed, R., Raghuraman, P., & Sudandiradoss, C. (2018) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2018.09.056 · Cited by 24
Takasugi, N., Komai, M., Kaneshiro, N., Ikeda, A., Kamikubo, Y., & Uehara, T. (2023) · Cells · doi:10.3390/cells12030454 · Cited by 29
“The partial knockout of APP [94] or Figure 5.”
BackgroundAlldred, M. J., Pidikiti, H., Heguy, A., Roussos, P., & Ginsberg, S. D. (2023) · The FASEB Journal · doi:10.1096/fj.202202111rr · Cited by 21
Gautier, M. K., Kelley, C. M., Lee, S. H., Alldred, M. J., McDaid, J., Mufson, E. J., Stutzmann, G. E., & Ginsberg, S. D. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106332 · Cited by 21
“Pathological accumulation of early endosomes in the cell soma and proximal dendrites of BFCNs of the MSN/VDB is observable in Ts65Dn mice by 6 – 8 MO (Cataldo et al., 2003; Jiang et al., 2016; Salehi et al., 2006).”
Bridging the age spectrum of neurodegenerative storage diseases
Boland, B., & Platt, F. M. (2014) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2014.08.009 · Cited by 24
Focusing 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
Xing, Z., Li, Y., Cortes-Gomez, E., Jiang, X., Gao, S., Pao, A., Shan, J., Song, Y., Perez, A., Yu, T., et al. (2023) · Human Molecular Genetics · doi:10.1093/hmg/ddad056 · Cited by 23
Gryaznova, T., Gubar, O., Burdyniuk, M., Kropyvko, S., & Rynditch, A. (2018) · Gene · doi:10.1016/j.gene.2018.06.078 · Cited by 18
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
Aboud, O., Parcon, P. A., DeWall, K. M., Liu, L., Mrak, R. E., & Griffin, W. S. T. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00103 · Cited by 23
“It is also important to note that in both Alzheimer’s and Down’s syndrome, endosomal changes are among the earliest pathological anomalies (Cataldo et al., 1996, 2003), suggesting that failures in this system are particularly powerful as they occur early and are persistent, with middle and end…”
BackgroundTc1 mouse model of trisomy-21 dissociates properties of short- and long-term recognition memory
Hall, J. H., Wiseman, F. K., Fisher, E., Tybulewicz, V. L. J., Harwood, J. L., & Good, M. A. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.02.002 · Cited by 26
“Although speculative, this pattern of results suggests that aberrant APP expression (perhaps in combination with other genes, see Cataldo et al., 2003) may contribute to impaired long-term object and place recognition memory deficits in Ts65Dn and that other genes may have an impact on short-term…”
BackgroundRole of metal ions in the cognitive decline of Down syndrome
Malakooti, N., Pritchard, M. A., Adlard, P. A., & Finkelstein, D. I. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00136 · Cited by 20
“No change in the endosomal phenotype was observed indicating other factors are necessary for this alteration (Cataldo et al., 2003).”
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
“Interestingly, by morphometric analysis, the number of early endosome-associated protein-1–positive endosomes of all sizes is increased in primary fibroblast from DS patients compared to diploid controls, and the majority of them were identified particularly as large-sized endosomes.(38) In DS retromer complex functio…”
BackgroundExploring the potential role of rab5 protein in endo-lysosomal impairment in Alzheimer’s disease
Behl, T., Kaur, D., Sehgal, A., Singh, S., Makeen, H. A., Albratty, M., Abdellatif, A. A. H., Dachani, S. R., & BUNGAU, S. G. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112773 · Cited by 20
Tallino, S., Winslow, W., Bartholomew, S. K., & Velázquez, R. (2022) · Aging Cell · doi:10.1111/acel.13590 · Cited by 15
The Use of Mouse Models for Understanding the Biology of Down Syndrome and Aging
Vacano, G. N., Duval, N., & Patterson, D. W. (2012) · Current Gerontology and Geriatrics Research · doi:10.1155/2012/717315 · Cited by 26
“Early endosomal alterations are the earliest known pathology in sporadic AD and DS [142].”
BackgroundNovokhatska, O., Dergai, M., Tsyba, L., Skrypkina, I., Filonenko, V. V., Moreau, J., & Rynditch, A. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070546 · Cited by 19
“Enlarged early endosomes were found in patients with Alzheimer’s disease, Down syndrome individuals and animal model of Down syndrome [7,8].”
BackgroundBriggs, J., Mason, E. A., Ovchinnikov, D. A., Wells, C. A., & Wolvetang, E. J. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2012-0117 · 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).”
ResultKaur, G., Gauthier, S. A., Pérez‐González, R., Pawlik, M., Singh, A. B., Cosby, B., Mohan, P. S., Smiley, J. F., & Levy, E. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.08.025 · Cited by 17
Nosheny, R. L., Belichenko, P. V., Busse, B. L., Weissmiller, A. M., Dang, V., Das, D., Fahimi, A., Salehi, A., Smith, S. J., & Mobley, W. C. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.02.022 · Cited by 17
“Enlarged endosomes are also present in neurons in Ts65Dnmice (Cataldo et al., 2003; Salehi et al., 2006).”
BackgroundDown syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21
Ruparelia, A., Wiseman, F. K., Sheppard, O., Tybulewicz, V. L. J., & Fisher, E. (2010) · Journal of Biomedical Research · doi:10.1016/s1674-8301(10)60016-4 · Cited by 17
“Increased APP expression is also linked to enlargement of early endosomes([92,95-99]).”
BackgroundResultArriagada, C., Astorga, C., Atwater, I. J., Rojas, E., Mears, D. J., Caviedes, R., & Caviedes, P. A. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.06.054 · Cited by 16
Pérez‐González, R., Gauthier, S. A., Sharma, A., Miller, C., Pawlik, M., Kaur, G., Kim, Y., & Levy, E. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.07.016 · Cited by 15
“These findings emphasize the critical role of APP in the development of these abnormalities as previously suggested (Cataldo et al., 2003; Salehi et al., 2006).”
Sukreet, S., Rafii, M. S., & Rissman, R. A. (2024) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12580 · Cited by 13
“130,141,142 The endocytic pathway is also responsible for sEVs formation and release, and trisomic APP boosts the boosted exosome release in extracellular space. sEVs are believed to have a compensatory and protective function in neurodegeneration by clearing toxic content from neurons.”
BackgroundArriagada, C., Bustamante, M., Atwater, I. J., Rojas, E., Caviedes, R., & Caviedes, P. A. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.12.062 · Cited by 15
Guix, F. X., Sartório, C. L., & ILL‐Raga, G. (2019) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-180089 · Cited by 13
“A segmental trisomy 16 mouse model of DS present endosomal abnormalities and impaired NGF axonal transport, similar to the findings in A PP-over expressing basal forebrain cholinergic neurons [224, 226, 227].”
ResultBarthelson, K., Pederson, S., Newman, M., & Lardelli, M. T. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-201383 · Cited by 12
Astrocytes of the murine model for Down Syndrome Ts65Dn display reduced intracellular ionic zinc
Ballestín, R., Blasco‐Ibáñez, J. M., Crespo, C., Nácher, J., López‐Hidalgo, R., Gilabert‐Juan, J., Moltó, D., & Varea, E. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.05.013 · Cited by 11
Stimuli-Sensitive Nanosystems: For Drug and Gene Delivery
Kang, H. C., Lee, E. S., Na, K., & Bae, Y. H. (2008) · Fundamental biomedical technologies · doi:10.1007/978-0-387-76554-9_6 · Cited by 11
“The drug resistance of certain tumors to cytotoxic agents observed from the beginning of chemotherapy was often linked to the expression of multidrug efflux pumps (P-glycoprotein (Pgp) or MDRassociated proteins), altered glutathione metabolism, reduced topoisomerase II activity, and various changes in cellular protein…”
BackgroundThe Link Between Lysosomal Storage Disorders and More Common Diseases
Beck, M. (2016) · Journal of Inborn Errors of Metabolism and Screening · doi:10.1177/2326409816682767 · Cited by 11
“In some families, the duplication of the amyloid precursor protein (APP) gene is the cause of early-onset Alzheimer disease, and in an animal model of Down syndrome, it was shown that the triplication of the APP gene leads to the dysfunction of the endocytic pathway, resulting in defective neurotrophic signaling and n…”
BackgroundThe Role of RIN3 Gene in Alzheimer’s Disease Pathogenesis: a Comprehensive Review
Meshref, M. M., Ghaith, H. S., Hammad, M. A., Shalaby, M. M. M., Ayasra, F., Monib, F. A., Attia, M. S., Ebada, M. A., Elsayed, H., Shalash, A., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03802-0 · Cited by 12
“Studies of donated human tissues carried out via Cataldo et al. demonstrated that at the prodromal stages of AD, abundant neurons have a raised Aβ peptide deposition and show early Rab-5 positive endosomal enlargement [129, 130].”
BackgroundAssembly and disassembly dynamics of nonmuscle myosin II control endosomal fission
Kar, J., Kar, S., Gupta, A., & Jana, S. S. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112108 · Cited by 10
Nižetić, D., Chen, C., Hong, W., & Koo, E. H. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00299 · Cited by 9
“Similarly, endosomal abnormalities in the form of enlarged organelles which are characteristic changes in brains of both AD and DS individuals and also a consequence of increased APP expression (Cataldo et al., 2003).”
BackgroundChromosomal Abnormalities - A Hallmark Manifestation of Genomic Instability
Larramendy, M. L., & Soloneski, S. (2017) · InTech eBooks · doi:10.5772/65142 · Cited by 9
Gautier, M. K., Kelley, C. M., Lee, S. H., Mufson, E. J., & Ginsberg, S. D. (2024) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2024.09.002 · Cited by 8
“These mice survive until adulthood and recapitulate key aspects of human DS neuropathology including early endosomal abnormalities (Cataldo et al., 2003), altered amyloid-beta precursor protein (APP) expression (Choi et al., 2009; Seo and Isacson, 2005), and degeneration of BFCNs (Hamlett et al.,…”
BackgroundPizzano, S., Sterne, G. R., Veling, M. W., Xu, L. A., Hergenreder, T., & Ye, B. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.049725 · Cited by 7
“…that, in DS models, increased APP expression causes an increase in RAB5 activation (Xu et al., 2016), which creates enlarged early endosomes and may contribute to the AD commonly seen in DS patients (DS-AD) (Cataldo et al., 2003; Cattaneo and Calissano, 2012; Salehi et al., 2006; Xu et al., 2016).”
InfluentialAlldred, M. J., Pidikiti, H., Ibrahim, K. W., Lee, S. H., Heguy, A., Hoffman, G. E., Roussos, P., Wısnıewskı, T., Węgiel, J., Stutzmann, G. E., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02768-0 · Cited by 8
“Trisomy of the amyloid precursor protein (APP) gene drives the formation of senile plaques in DS [36, 40, 52, 103], and has long thought to be a target for therapeutics.”
Alldred, M. J., Ibrahim, K. W., Pidikiti, H., Chiosis, G., Mufson, E. J., Stutzmann, G. E., & Ginsberg, S. D. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01891-z · Cited by 7
“While several trisomic genes have been implicated in AD pathology or memory impairments, including amyloid precursor protein (APP) [21, 23, 30, 78], dual specificity tyrosine phosphorylation regulated kinase 1 A (DYRK1A) [25, 43], transmembrane serine protease 2 (TMPRSS2) [2], and 4 of the 6 known…”
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
“, 2020), as well as in the most commonly used mouse model of DS, Ts65Dn (Cataldo et al., 2003), thus overall indicating the critical role of the endosomal pathway in DS.”
BackgroundLo, K., Wang, L., Chen, I.-J., Liu, Y., Chung, M., & Lo, W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114617 · Cited by 7
“Mouse models of Down syndrome, Ts65Dn and Ts1Cje, show a connection between the high-grade aneuploidy and cellular alterations in protein degradation and aging [64].”
BackgroundAssessing Rab5 Activation in Health and Disease
Pensalfini, A., Jiang, Y., Kim, S., & Nixon, R. A. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1346-7_20 · Cited by 7
Self-citationCyclic cis-Locked Phospho-Dipeptides Reduce Entry of AβPP into Amyloidogenic Processing Pathway
Fisher, C. L., Resnick, R. J., De, S., Acevedo, L. A., Lu, K. P., Schroeder, F. C., & Nicholson, L. K. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160051 · Cited by 10
“Cleavage of A PP by BACE1 is enhanced by elevated BACE1 expression [16], by elevated A PP gene dosage such as in trisomy 21 individuals [17, 18], by familial A PP mutations [19], and by cholesterol enrichment in membrane invaginations (reviewed in [20]).”
BackgroundCholinergic Neurodegeneration in Alzheimer's Disease: Basis for Nerve Growth Factor Therapy
Salehi, A., Kleschevnikov, A. M., & Mobley, W. C. (2007) · Springer eBooks · doi:10.1007/978-0-387-71522-3_5 · Cited by 7
Axonal Transport of Neurotrophic Signals: An Achilles' Heel for Neurodegeneration?
Salehi, A., Wu, C., Zhan, K., & Mobley, W. C. (2009) · Research and perspectives in Alzheimer's disease · doi:10.1007/978-3-540-87941-1_7 · Cited by 7
“reported in both DS and early AD (Cataldo et al. 2003; Cui et al. 2007).”
BackgroundImpaired BDNF-TrkB trafficking and signalling in Down syndrome basal forebrain neurons
Blackburn, E., Birsa, N., Lopes, A. T., Fisher, E., Lazo, O. M., & Schiavo, G. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08464-z · Cited by 7
Acuña, M. A., Pérez-Núñez, R., Noriega, J., et al. (2011) · Neurotoxicity Research · doi:10.1007/s12640-011-9304-5 · Cited by 5
“Increased half life in the membrane of such channels may underlie increased channel density, a possibility that arises from the reduced membrane internalization and endosomal abnormalities reported in other DS models (Cataldo et al. 2003; 2004) as well as in the CTb cell line (Arriagada et al.”
BackgroundCan Green Tea Polyphenols Improve Phenotypes Associated With Down Syndrome?
Roper, R. J., & Goodlett, C. R. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813008-7.00035-7 · Cited by 5
Dynamic changes in lysosome‐related pathways in APP/PS1 mice with aging
Xu, Z., Hu, J., Wei, Z. C., Yu, L., Afewerky, H. K., Gao, Y., Wan, L., Li, L., Ling, L., Liu, Y., et al. (2024) · MedComm · doi:10.1002/mco2.540 · Cited by 4
“9 Endosomal dysfunction is also observed in neurons of patients with early-stage AD, 8 Additionally, an electron microscopy-based study found that the number of abnormal endosomes was increased in triploid APP transgenic mice, a commonly used animal model of AD, 10 This finding further emphasizes that abnormal APP met…”
InfluentialMolecular Pathways of Down Syndrome Critical Region Genes
Di, F., & Berto, G. E. (2013) · InTech eBooks · doi:10.5772/53000 · Cited by 6
Small-molecule aggregation inhibitors reduce excess amyloid in a trisomy 16 mouse cortical cell line
Paula-Lima, A. C., Arriagada, C., Toro, R., Cárdenas, A. M., Caviedes, R., Ferreira, S. T., & Caviedes, P. A. (2008) · Biological Research · doi:10.4067/s0716-97602008000200001 · Cited by 5
Synaptic Vesicle Recycling Is Unaffected in the Ts65Dn Mouse Model of Down Syndrome
Marland, J. R. K., Smillie, K. J., & Cousin, M. A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147974 · Cited by 5
“Comparative studies in trisomic neurons have highlighted increases in presynaptic and postsynaptic size [31], presence of enlarged endosomal structures [32], and alterations in neuronal intracellular trafficking [33].”
BackgroundInfluentialThe Lysosome in Aging‐Related Neurodegenerative Diseases
Nixon, R. A. (2016) · Wiley eBooks · doi:10.1002/9781118978320.ch9 · Cited by 5
Self-citationFatemi, S. H., Otte, E. D., Folsom, T. D., Eschenlauer, A. C., Roper, R. J., Aman, J. W., & THURAS, P. D. (2024) · Genes · doi:10.3390/genes15040452 · Cited by 4
“Morphologically, this animal model also displays reduced brain volume, reduced neuronal density, reduced cerebellar volume, impaired neurogenesis, reduced dendritic density, and endosomal abnormalities similar to brain abnormalities in individuals with DS [18–25].”
BackgroundRCAN1 and Its Potential Contribution to the Down Syndrome Phenotype
Melanie, A., & Katherine, R. (2013) · InTech eBooks · doi:10.5772/52977 · Cited by 4
“Other examples under study with a particular focus on brain function include, DYRK1A [5], SOD1 [6], APP [7] [8] [9], SNYJ1 [10] and ITSN1 [11].”
BackgroundCofilin-mediated neurodegeneration in alzheimer’s disease and other amyloidopathies
Maloney, M. T., & Bamburg, J. R. (2007) · Molecular Neurobiology · doi:10.1007/s12035-007-0009-y · Cited by 4
Cannavo, C., Tosh, J., Fisher, E., & Wiseman, F. K. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.004 · Cited by 4
APP Biology, Processing and Function
Thinakaran, G., & Koo, E. H. (2007) · Springer eBooks · doi:10.1007/978-0-387-35135-3_2 · Cited by 4
“Interestingly, these changes can be reversed if the APP gene dosage was reduced back to the euploid state when the Ts65Dn mice were crossed to the APP-deficient animals, showing that these changes are uniquely due to APP gene dosage (Cataldo et al., 2003).”
BackgroundAlldred, M. J., Ibrahim, K. W., Pidikiti, H., Lee, S. H., Heguy, A., Chiosis, G., Mufson, E. J., Stutzmann, G. E., & Ginsberg, S. D. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1546375 · Cited by 4
Excess βCTF, not Aβ: The culprit in Alzheimer-related endocytic dysfunction
Griffin, W. S. T. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913922107 · Cited by 3
“Both of these abnormalities and degenerative changes of basal forebrain cholinergic neurons are ameliorated by suppressing the overexpression of βAPP (13, 14).”
BackgroundRuparelia, A., & Mobley, W. C. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-398270-4.00005-7 · Cited by 4
Jiang, Y., Sachdeva, K., Goulbourne, C. N., Berg, M. J., Peddy, J., Stavrides, P. H., Pensalfini, A., Pawlik, M., Malampati, S., Whyte, L. S., et al. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.2331-24.2025 · Cited by 2
“Mouse disease models typically show measurable BFCN degeneration months following detectable endosomal alterations (Cataldo et al., 2000, 2003; Salehi et al., 2006; Choi et al., 2009; Jiang et al., 2016, 2022; Pensal fi ni et al., 2020).”
Self-citation
Metadata
- Authors
- Cataldo, A. M., Petanceska, S., Peterhoff, C. M., Terio, N. B., Epstein, C. J., Villar, A., Carlson, E. J., Staufenbiel, M., & Nixon, R. A.
- Affiliations
- Harvard University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-07-30
- Volume
- 23
- Issue
- 17
- Pages
- 6788-6792
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740714
- OpenAlex
- W1900601199
- Cited by
- 241
- References
- 27
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 11 · 2022: 9 · 2021: 7 · 2020: 17 · 2019: 16 · 2018: 11 · 2017: 11 · 2016: 9 · 2015: 14 · 2014: 19 · 2013: 11 · 2012: 7
- FWCI
- 3.26
- 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 Institutes of Health (5r01hd031498-05, AG17617)
- National Institute on Aging (P01AG017617, AG17617)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-31498)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- Alzheimer's disease, Down syndrome, Ts65Dn mouse model, early endosomes, endosome fusion, endosome recycling, Rab5, Rab4, EEA1, amyloid-beta, basal forebrain, neuronal atrophy, gene triplication
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Brain Chemistry, Disease Models, Animal, Down Syndrome, Endocytosis, Humans, Membrane Proteins, Mice, Neurologic Mutants, Mice, Transgenic, Neurons, Phenotype, Endosomes, Trisomy, Prosencephalon, Amyloid beta-Protein Precursor, Sequence Deletion, Disease Progression, Gene Dosage, rab5 GTP-Binding Proteins, Mice, Presenilin-1
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