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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
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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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- Partly supported
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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.
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- 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.
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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.
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- Partly supported
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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.
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- 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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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.
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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.
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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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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.
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In the paper
“Western blot analysis, which revealed a 2.5-fold increase in rab4 levels ( p Ͻ 0.0006; n ϭ 4).”
§ 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.
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In the paper
“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.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Abstract
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, both the Ts65Dn-App ϩ/ϩ/Ϫ and Ts1Cje mice expressed rab4 immunoreactivity at levels similar to those in neurons from agematched littermate controls.”
§ 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.
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In the paper
“Basal forebrain neurons from both of these lines of App transgenic mice had normal-appearing vesicular rab5-positive early endosomes (Fig. 4) and patterns of immunolabeling for the other endosomal markers EEA1, rab4, and rabaptin5, similar to those in 2N controls.”
§ 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.
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In the paper
“Neurons from Ts65Dn mice displayed rab5-positive early endosomes of abnormally large sizes (Fig. 1), which were similar morphologically to those seen in human DS brain as early as 2 months of age.”
§ 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.
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In the paper
“Early endosomes in the same neuronal populations appeared as the typical, small, and uniform vesicular compartments in 2N littermate control mice (Fig. 1).”
§ 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
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Endosomal enlargement was detected in fewer neurons within the amygdala, cingulate cortex, and hippocampus from Ts65Dn 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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“As seen in neurons from infants and fetuses with trisomy 21 (Cataldo et al., 2000b), we also found intraneuronal A within rab5-positive vesicular compartments of neurons from Ts65Dn mice.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
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In the paper
“Our findings show that Ts65Dn mice develop neuronal endosome abnormalities strongly resembling the highly AD-specific endocytic alterations that develop at the earliest stages of AD.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
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In the paper
“and further establish the pathogenic significance of endosomal dysfunction in AD.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Abstract
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In the paper
“Ts65Dn mice with a segmental trisomy extending from App to Mx1 exhibit behavioral and cognitive abnormalities not unlike some of the abnormalities seen in individuals with DS (Reeves et al., 1995).”
§ 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 Reeves et al., 1995 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar endosomal abnormalities, when modeled in cells, are associated with increased A production (Grbovic et al., 2002).”
§ 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 matchedcites Grbovic et al., 2002
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.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“implying that one or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Despite the lack of development of late-stage pathology in Ts65Dn mice, the association between endosomal disturbances and basal forebrain neuronal atrophy and its close relationship to App gene dosage support the use of Ts65Dn mice as a valuable model in which to investigate the key early events of AD pathogenesis.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
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In the paper
“implying that functionally, endosomal uptake and fusion were increased.”
§ 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.
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In the paper
“We have shown that the development of early endosomal abnormalities in Ts65Dn mice is dependent on App gene triplication.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Discussion
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In the paper
“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.”
§ App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome > Abstract
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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.
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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.
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- 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)
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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.
- 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
“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.
- 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
“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.
- Based: passes — The paper gives a reason why it holds.
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.
- 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
“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
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- 2002, Neurobiol Aging, 23, 50
- 1998, Nat Med, 1, 97
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Lawrence, R. E., & Zoncu, R. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0244-7 · Cited by 920
Autophagy failure in Alzheimer's disease—locating the primary defect
Nixon, R. A., & Yang, D.-S. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.01.021 · Cited by 595
Self-citationAmyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580
Salehi, A., Delcroix, J.-D., Belichenko, P. V., Zhan, K., Wu, C., Valletta, J. S., Takimoto-Kimura, R., Kleschevnikov, A. M., Sambamurti, K., Chung, P. P., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.05.022 · Cited by 543
“In view of earlier studies linking enlargement of EEs and App gene dose in the Ts65Dn mouse (Cataldo et al., 2003), and the important role played by EEs in retrograde transport of NGF and its signals (Delcroix et al.”
InfluentialSelf-citationAlzheimer disease models and human neuropathology: similarities and differences
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“There is no enlargement of the endosomes in the Ts1Cje mice (no APP overexpression) andor in transgenic mice overexpressing APP751 with the Swedish double mutation alone or in combination with the London mutation [49].”
Background
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-27, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-27 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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