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
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A mouse model for Down syndrome exhibits learning and behaviour deficits
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Self-citationApoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro
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β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity
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The lysosome as a cellular centre for signalling, metabolism and quality control
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
Duyckaerts, C., Potier, M.-C., & Delatour, B. (2008) · Acta Neuropathologica · doi:10.1007/s00401-007-0312-8 · Cited by 375
“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].”
BackgroundThe early endosome: a busy sorting station for proteins at the crossroads.
Jović, M., Sharma, M., Rahajeng, J., & Caplan, S. (2010) · PubMed · doi:10.14670/hh-25.99 · Cited by 380
Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases
Nixon, R. A. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.09.018 · Cited by 380
“Significantly, these endocytic abnormalities are eliminated when the Ts65Dn mice are made diploid for APP [ 15 ], establishing a direct relationship between this AD-related gene and endosome dysfunction.”
BackgroundSelf-citationNeurodegenerative lysosomal disorders: A continuum from development to late age
Nixon, R. A., Yang, D.-S., & Lee, J.-H. (2008) · Autophagy · doi:10.4161/auto.6259 · Cited by 362
Self-citationCataldo, A. M., Petanceska, S., Terio, N. B., Peterhoff, C. M., Durham, R., Mercken, M., Mehta, P. D., Buxbaum, J., Haroutunian, V., & Nixon, R. A. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.02.027 · Cited by 363
“The appearance of these abnormalities is promoted by APOE4 [4] and, in a mouse model of Down syndrome, requires App triplication [5].”
BackgroundSelf-citationJiang, Y., Mullaney, K. A., Peterhoff, C. M., Che, S., Schmidt, S. D., Boyer‐Boiteau, A., Ginsberg, S. D., Cataldo, A. M., Mathews, P. M., & Nixon, R. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908953107 · Cited by 293
“Our observations in DS fibroblasts agree with findings in Ts65Dn mice, in which selective deletion of 1 copy ofApp or a small portion of theMNU16 segment containing App reverses both neuronal endosomal pathology (17) anddegenerative changes in basal forebrain cholinergic neuron (16).”
BackgroundResultInfluentialSelf-citationChen, X., & Mobley, W. C. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00659 · Cited by 302
“Endosomal phenotypes also impact many neurons in the brain of a segmental trisomy 16 mouse model of DS, the Ts65Dn mouse, including neurons in neocortex, hippocampus as well as the medial septal nucleus (MSN), and NBM of basal forebrain (Cataldo et al., 2003).”
BackgroundDYRK1A-mediated Hyperphosphorylation of Tau
Ryoo, S., Jeong, H. K., Radnaabazar, C., Yoo, J.-J., Cho, H.-J., Lee, H. W., Kim, I.-S., Cheon, Y. H., Ahn, Y. S., Chung, S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707358200 · Cited by 285
Amyloid-Independent Mechanisms in Alzheimer's Disease Pathogenesis
Pimplikar, S. W., Nixon, R. A., Robakis, N. K. R. K., Shen, J., & Tsai, L. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4305-10.2010 · Cited by 287
“…and in Down syndrome, where a chromosome 21 segment containing App is trisomic, endosome dysfunction can be attributed to the extra copy of App (Cataldo et al., 2003; Salehi et al., 2006; Jiang et al., 2010) and has been linked to altered trophic signaling and cholinergic neurodegeneration…”
BackgroundInfluentialSelf-citationMolecular genetic analysis of Down syndrome
Patterson, D. (2009) · Human Genetics · doi:10.1007/s00439-009-0696-8 · Cited by 278
“Mice in which individual genes trisomic in these mice have been knocked out can be bred with trisomic mice to bring particular genes back to the diploid state in a context in which all the other genes remain trisomic (e.g., Cataldo et al. 2003; Sussan et al. 2008).”
BackgroundThe multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes
Nhan, H. S., Chiang, K., & Koo, E. H. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1347-2 · Cited by 272
Gene expression profiling in the adult Down syndrome brain
Lockstone, H. E., Harris, L. W., Swatton, J. E., Wayland, M. T., Holland, A. J., & Bahn, S. (2007) · Genomics · doi:10.1016/j.ygeno.2007.08.005 · Cited by 240
“Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 has been proposed as the central event leading to AD pathology in DS [1,2], in keeping with the amyloid cascade hypothesis [27,28], but evidence suggests that triplication of this gene alone is not sufficient for the development of AD patholog…”
BackgroundA mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions
Yu, T., Li, Z., Jia, Z., Clapcote, S. J., Liu, C., Li, S., Asrar, S., Pao, A., Chen, R., Fan, N., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq179 · Cited by 248
Ryoo, S., Cho, H., Lee, H. W., Jeong, H. K., Radnaabazar, C., Kim, Y., Kim, M., Son, M., Seo, H., Chung, S., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05075.x · Cited by 238
Alzheimer disease and Down syndrome: factors in pathogenesis
Lott, I. T., & Head, E. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.08.005 · Cited by 212
“[5] Cataldo AM, Petanceska S, Peterhoff CM, Terio NB, Epstein CJ, Villar A, et al.”
BackgroundResultSchneider, A., Rajendran, L., Honsho, M., Gralle, M., Donnert, G., Wouters, F. S., Hell, S. W., & Simons, M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5345-07.2008 · Cited by 222
“…the neuronal sortilin-related receptor, Sorl1, a protein involved in the regulation of the endosomal trafficking of APP (Spoelgen et al., 2006; Rogaeva et al., 2007) and the known endocytic pathway abnormalities in Alzheimer’s disease (Cataldo et al., 2003; Nixon, 2005; Laifenfeld et al., 2007).”
BackgroundDown syndrome and genetics — a case of linked histories
Patterson, D., & Costa, A. C. S. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1525 · Cited by 220
Down Syndrome Fibroblast Model of Alzheimer-Related Endosome Pathology
Cataldo, A. M., Mathews, P. M., Boyer‐Boiteau, A., Hassinger, L. C., Peterhoff, C. M., Jiang, Y., Mullaney, K. A., Neve, R. L., Gruenberg, J. E., & Nixon, R. A. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.071053 · Cited by 188
Self-citationActin dynamics and cofilin‐actin rods in alzheimer disease
Bamburg, J. R., & Bernstein, B. W. (2016) · Cytoskeleton · doi:10.1002/cm.21282 · Cited by 181
“Chromosome 21 carries genes for APP, and DS patients have increased APP expression [Cataldo et al., 2003], which combined with the increase in BACE-1 activity occurring in DS patients, contributes to excess Ab production [Sun et al., 2006a,b].”
BackgroundXu, W. L., Weissmiller, A. M., White, J. A., Fang, F., Wang, X., Wu, Y., Pearn, M. L., Zhao, X., Sawa, M., Chen, S., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci82409 · Cited by 180
Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia
Marzia Perluigi, A., & Butterfield, D. A. (2011) · Current Gerontology and Geriatrics Research · doi:10.1155/2012/724904 · Cited by 190
“Neuroinflammation [68], endosomal dysfunction [69], and oxidative damage [52] may play a crucial role in DS as well as in AD pathology [66].”
BackgroundCytoskeletal pathologies of Alzheimer disease
Bamburg, J. R., & Bloom, G. S. (2009) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.20388 · Cited by 175
“Enlarged early endosomes develop in neurons before birth in DS brains [Cataldo et al., 2003] and appear years before significant formation of Ab deposits and Cytoskeletal Pathologies of AD 637”
Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99)
Jiang, Y., Sato, Y., Im, E., Berg, M., Bordi, M., Darji, S., Kumar, A., Mohan, P. S., Bandyopadhyay, U., Diaz, A., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0578-19.2019 · Cited by 166
“…neuropathological abnormalities equivalent in type and onset to those in the Ts65Dn trisomy model of DS, including APP-dependent neuronal endosomal anomalies (Cataldo et al., 2003), cholinergic neurodegeneration (Jiang et al., 2016), and glutamatergic neuronal deficits (Kaur et al., 2014).”
BackgroundSelf-citationSubcellular Topography of Neuronal Aβ Peptide in APPxPS1 Transgenic Mice
Langui, D., Girardot, N., El Hachimi, K. H., Allinquant, B., Blanchard, V., Pradier, L., & Duyckaerts, C. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63405-0 · Cited by 165
Colacurcio, D. J., Pensalfini, A., Jiang, Y., & Nixon, R. A. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.001 · Cited by 167
“studies have shown that Ts2 mice develop a similar regional pattern of APP-dependent neuronal endosomal abnormality [20,80], and a similar loss of basal forebrain cholinergic neurons (BFCN) as seen in Ts65Dn mice at the similar age [38,39,57,68].”
ResultSelf-citationCataldo, A. M., Peterhoff, C. M., Schmidt, S. D., Terio, N. B., Duff, K., Beard, M. E., Mathews, P. M., & Nixon, R. A. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.8.821 · Cited by 157
“Immunocytochemical studies were performed on 40-mm vibratome sections of aldehyde-fixed tissue from human and mouse frontal cortex (21, 35) using a polyclonal antibody directed against human liver Cat D (Dako Corporation, Carpinteria, CA) for human studies and an affinity-purified rabbit polyclonal antibody raised aga…”
MethodSelf-citationVoronov, S. V., Frere, S. G., Giovedi, S., Pollina, E. A., Borel, C., Zhang, H., Schmidt, C., Akeson, E. C., Wenk, M. R., Cimasoni, L., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803756105 · Cited by 174
“Future work should address whether a perturbation of this lipid is also involved in cognitive decline, paralleling the development of Alzheimer’s disease in individuals with DS (23, 24).”
BackgroundAneuploidy: implications for protein homeostasis and disease
Oromendia, A. B., & Amon, A. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.013391 · Cited by 157
“…is likely to be the additional copy of the APP gene encoded by chromosome 21 (reviewed in Kingsbury et al., 2006), mice overexpressing APP (which encodes amyloid beta A4 protein) do not fully recapitulate all the AD-like phenotypes seen in Down syndrome mouse models (Cataldo et al., 2003).”
BackgroundInfluentialEndo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?
Whyte, L. S., Lau, A. A., Hemsley, K. M., Hopwood, J. J., & Sargeant, T. J. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13935 · Cited by 150
Down syndrome: searching for the genetic culprits
Lana‐Elola, E., Watson-Scales, S., Fisher, E., & Tybulewicz, V. L. J. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.008078 · Cited by 145
“By contrast, overexpression of APP alone results in defective NGF transport but does not cause BFCN degeneration (Cataldo et al., 2003; Salehi et al., 2006).”
BackgroundThe endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo
Nuriel, T., Peng, K. Y., Ashok, A., Dillman, A. A., Figueroa, H. Y., Apuzzo, J., Ambat, J., Levy, E., Cookson, M. R., Mathews, P. M., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00702 · Cited by 140
“This magnitude of early endosome change is similar to that which was reported in Down syndrome mouse models (Cataldo et al., 2003), and is similar to the APOE4-dependent early endosomal alteration seen in human neurons in the prefrontal cortex in early-stage AD (Cataldo et al.”
ResultNiemann-Pick Type C Disease and Alzheimer's Disease
Nixon, R. A. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63163-x · Cited by 142
“The studies reported by Jin et al(12) in this issue of The American Journal of Pathology tie the cellular mechanisms operating in NPC and early stage AD even more tightly by showing that amyloidogenic processing of APP in NPC neurons localizes to early endosomes, a compartment of the endocytic pathway that develops th…”
BackgroundSelf-citationMoon, J., Chen, M. W., Gandhy, S. U., Strawderman, M. S., Levitsky, D. A., Maclean, K. N., & Strupp, B. J. (2010) · Behavioral Neuroscience · doi:10.1037/a0019590 · Cited by 134
“, 2006), due, in part, to triplication of App (Cataldo et al., 2003; Salehi et al., 2006).”
Nistor, M., Don, M., Parekh, M., Sarsoza, F. M., Goodus, M. T., López, G., Kawas, C. H., Leverenz, J. B., Doran, E. W., Lott, I. T., et al. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.06.023 · Cited by 137
“For example, synaptic dysfunction may be a consequence of APP overexpression or increased Aβ [58,60], or other pathological molecular cascades may be engaged in DS that are associated with AD pathology such as neuroinflammation [18,19,21,59], endosomal dysfunction [6,7] and oxidative damage [45,46].”
BackgroundCommunication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome
Contestabile, A., Benfenati, F., & Gasparini, L. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.003 · Cited by 134
“, 2006) through axonal mechanisms resulting in enlargement of early endosomes and bAPP overload (Cataldo et al., 2003; Chang and Gold, 2008; Salehi et al., 2006).”
InfluentialGinsberg, S. D., Mufson, E. J., Alldred, M. J., Counts, S., Wuu, J., Nixon, R. A., & Che, S. (2011) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2011.05.012 · Cited by 132
“The endosomal system is also perturbed in relevant animal models, including the Ts65Dn mouse model of DS and AD, with amyloid-beta precursor protein (APP) being required for the manifestation of the early endosome enlargement phenotype (Cataldo et al., 2003; Salehi et al., 2006).”
Self-citationGinsberg, S. D., Mufson, E. J., Counts, S., Wuu, J., Alldred, M. J., Nixon, R. A., & Che, S. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101080 · Cited by 134
Self-citationDysregulation of protein trafficking in neurodegeneration
Wang, X., Huang, T., Bu, G., & Xu, H. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-31 · Cited by 125
“In previous studies, investigators found that both primary fibroblasts from DS individuals and neurons from DS mouse models exhibit abnormal endocytic and lysosomal trafficking [25,26].”
BackgroundGauthier, S. A., Pérez‐González, R., Sharma, A., Huang, F.-K., Alldred, M. J., Pawlik, M., Kaur, G., Ginsberg, S. D., Neubert, T. A., & Levy, E. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0466-0 · Cited by 125
“In support of an inter-relationship between exosomal release and endosomal pathology, CD63 knockdown also caused changes in endosomes of DS fibroblasts, characteristic of the endosomal abnormalities reported in DS patients [10], DS fibroblasts [8], and in DS mouse models [9, 26].”
BackgroundCholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model
Lockrow, J. P., Prakasam, A., Huang, P., Bimonte‐Nelson, H. A., Sambamurti, K., & Granholm, A. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.11.021 · Cited by 126
“, 1992) accumulates in vesicles known to build up in this model (Cataldo et al., 2003).”
Keating, D. J., Dubach, D., Zanin, M., Yu, Y., Martin, K., Zhao, Y.-F., Chen, C., Porta, S., Arbonés, M. L., Mittaz, L., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddm374 · Cited by 122
Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M. ‐., Feldman, G. L., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R. E., & Sima, A. A. F. (2010) · Brain · doi:10.1093/brain/awq071 · Cited by 117
“, 1985; Wisniewski and Wrzolek, 1988) and may be caused by overexpression of the APP gene, which is located on chromosome 21 (Cataldo et al., 2003).”
BackgroundCofilin-mediated neurodegeneration in alzheimer’s disease and other amyloidopathies
Maloney, M. T., & Bamburg, J. R. (2007) · Molecular Neurobiology · doi:10.1007/bf02700622 · Cited by 115
Mrak, R. E., & Griffin, W. S. T. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.7.679 · Cited by 111
“However, triplication of the bAPP gene alone does not reproduce the phenotype, suggesting that additional factors are necessary for the generation of Alzheimer pathology in partial trisomy 16 mice, and in trisomy 21 humans (32).”
BackgroundFurther understanding the connection between Alzheimer's disease and Down syndrome
Snyder, H. M., Bain, L. J., Brickman, A. M., Carrillo, M. C., Esbensen, A. J., Espinosa, J. M., Fernandez, F., Fortea, J., Hartley, S. L., Head, E., et al. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12112 · Cited by 105
Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities
Yu, Y., Chu, P., Bowser, D. N., Keating, D. J., Dubach, D., Harper, I. S., Tkalcevic, J., Finkelstein, D. I., & Pritchard, M. A. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn224 · Cited by 104
“After an analysis of the brain phenotypes in mice resulting from either over-expression of the APP wild-type protein (as in DS) or of a mutated version of APP that leads to Alzheimer-type pathology or by comparisons of the phenotypes in the brains of DS mouse models carrying three copies of App (Ts65Dn) or two copies…”
BackgroundSosa, L. J., Cáceres, A., Dupraz, S., Oksdath, M., Quiroga, S., & Lorenzo, A. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14122 · Cited by 118
Thomas, S., Ritter, B., Verbich, D., Sanson, C., Bourbonnière, L., McKinney, R. A., & McPherson, P. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809746200 · Cited by 105
Cossec, J., Lavaur, J., Berman, D. E., Rivals, I., Hoischen, A., Stora, S., Ripoll, C., Mircher, C., Grattau, Y., Olivo‐Marín, J., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds142 · Cited by 106
“In addition, App transgenic mice carrying the Swedish mutations do not show any endosomal dysfunction (8).”
InfluentialWang, M., Song, W., Chen, M., Wang, Q., Zhou, X., Xu, P., Krek, A., Yoon, Y., Ho, L., Orr, M. E., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00517-z · Cited by 104
Jiang, Y., Rigoglioso, A., Peterhoff, C. M., Pawlik, M., Sato, Y., Bleiwas, C., Stavrides, P., Smiley, J. F., Ginsberg, S. D., Mathews, P. M., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.11.013 · Cited by 97
“4G and H) in Ts2 mice at 4 months of age, and the enlargement is comparable to that seen in age-matched Ts65Dn mice (Cataldo et al., 2003).”
InfluentialSelf-citationStillman, A. A., Krsnik, Ž., Sun, J., Rašin, M., State, M. W., šestan, N., & Louvi, A. (2009) · Journal of Comparative Neurology · doi:10.1002/cne.21919 · Cited by 95
“…of rat and mouse brain lysates and transfected Rab5 protein in cells by immunocytochemistry (manufacturer’s technical information) and stained a pattern of cellular distribution in mouse brain identical to that in previous reports (Cataldo et al., 2003) and to the authors’ unpublished observations.”
ResultGinsberg, S. D., Alldred, M. J., & Che, S. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.07.013 · Cited by 88
Choi, J. H. K., Berger, J. D., Mazzella, M. J., Morales‐Corraliza, J., Cataldo, A. M., Nixon, R. A., Ginsberg, S. D., Levy, E., & Mathews, P. M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06277.x · Cited by 83
“Crossing the Ts65Dn mouse with a mouse carrying an APP null allele to restore App gene copy to 2N levels has shown that triplication of the App gene is necessary for the development of the abnormally large neuronal endosomes (Cataldo et al. 2003) and for the defective retrograde NGF trophic support seen in the Ts65Dn…”
BackgroundResultInfluentialSelf-citationIm, E., Jiang, Y., Stavrides, P. H., Darji, S., Erdjument-Bromage, H., Neubert, T. A., Choi, J. Y., Wegiel, J., Lee, J.-H., & Nixon, R. A. (2023) · Science Advances · doi:10.1126/sciadv.adg1925 · Cited by 80
Self-citationMolecular basis of pharmacotherapies for cognition in Down syndrome
Gardiner, K. (2009) · TIPS - Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.10.010 · Cited by 113
“First, when Ts65Dn mice were crossed with a knockout of the App gene, thus reducing App to disomy, the development of some cellular abnormalities, including degeneration of BFCN, was prevented [28,29].”
BackgroundExosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases
Mathews, P. M., & Levy, E. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01347 · Cited by 81
Is it possible to improve neurodevelopmental abnormalities in Down syndrome?
Bartesaghi, R., Guidi, S., & Ciani, E. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.037 · Cited by 77
“In particular, there is a reduced expression of the TRKBT.1 variant, a dominant, negative form of TRKB lacking the tyrosine kinase domain (Cataldo et al., 2003 ), and of the full-length TRKB (Toiber et al., 2010 ).”
BackgroundMethodStrupp, B. J., Powers, B. E., Velázquez, R., Ash, J. A., Kelley, C. M., Alldred, M. J., Strawderman, M. S., Caudill, M. A., Mufson, E. J., & Ginsberg, S. D. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666150921100311 · Cited by 72
“MCS also offered protection to BFCNs in the medial septal nucleus (MSN) [74], which typically exhibits atrophic changes by ~6 months of age [29, 36, 41, 113, 114].”
BackgroundChang, K. T., & Min, K. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904397106 · Cited by 77
“Di Paolo G, et al. (2004) Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking.”
BackgroundMethodInfluentialCritical importance of RAB proteins for synaptic function
Mignogna, M. L., & D’Adamo, P. (2017) · Small GTPases · doi:10.1080/21541248.2016.1277001 · Cited by 82
Mohajer, G., Lee, E. S., & Bae, Y. H. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9277-5 · Cited by 73
“Overall, this novel pH-sensitive polymeric micelle can provide not only for the targeting of tumor cells by folatereceptor recognition, but also for preserving high intracellular drug concentrations in both wild-type and resistant tumor cells.Uncited references: ( 4 , 15, 24, 35) Fig. 7. The relative DOX content (perc…”
MethodInfluentialOvchinnikov, D. A., Korn, O., Virshup, I., Wells, C. A., & Wolvetang, E. J. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.05.004 · Cited by 73
“, 2014) or overexpression of wild-type APP protein (Cataldo et al., 2003), also did not exhibit tau pathology.”
BackgroundUsing mouse models to explore genotype–phenotype relationship in Down syndrome
Salehi, A., Faizi, M., Belichenko, P. V., & Mobley, W. C. (2007) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.20164 · Cited by 70
“Ts65Dn: Appþ/ þ/2 are viable and have no gross nervous system abnormalities with normal life span [Cataldo et al., 2003]. Cataldo et al. [2003] studied the endosomal system in Ts65Dn mice (with three copies of App) and found enlarged early endosomes in the basal forebrain as early as 2 months.”
BackgroundResultDysregulation of Rab5‐mediated endocytic pathways in Alzheimer's disease
Xu, W. L., Fang, F., Ding, J., & Wu, C. (2018) · Traffic · doi:10.1111/tra.12547 · Cited by 72
The proteins of human chromosome 21
Gardiner, K., & Costa, A. C. S. (2006) · American Journal of Medical Genetics. Part C, Seminars in Medical Genetics · doi:10.1002/ajmg.c.30098 · Cited by 74
Jiang, Y., Alam, J. J., Gomperts, S. N., Maruff, P. T., Lemstra, A. W., Germann, U. A., Stavrides, P. H., Darji, S., Malampati, S., Peddy, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32944-3 · Cited by 65
Self-citationChen, X., Sawa, M., & Mobley, W. C. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.341 · Cited by 66
“Studies in mouse models of DS confirm the necessity for increased APP gene dose for agerelated degeneration of neurons that also degenerate in AD-DS [8, 107].”
BackgroundSynaptophysin and Synaptojanin-1 in Down Syndrome are Differentially Affected by Alzheimer's Disease
Martin, S. B., Dowling, A. L. S., Lianekhammy, J., Lott, I. T., Doran, E., Murphy, M. P., Beckett, T. L., Schmitt, F. A., & Head, E. (2014) · Journal of Alzheimer's Disease · doi:10.3233/jad-140795 · Cited by 64
The Involvement of Lipids in Alzheimer's Disease
Lim, W. L. F., Martins, I. J., & Martins, R. N. (2014) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2014.04.003 · Cited by 67
“Many lipid and protein studies have led to findings of endosomal dysfunction in metabolic diseases as well as in AD (Cataldo et al., 2003; Zehmer et al., 2009; Yu et al., 2010; Treusch et al., 2011).”
BackgroundRole of Tau Protein in Neuronal Damage in Alzheimer's Disease and Down Syndrome
Cárdenas, A. M., Ardiles, Á. O., Barraza, N., Báez‐Matus, X., & Caviedes, P. A. (2012) · Archives of Medical Research · doi:10.1016/j.arcmed.2012.10.012 · Cited by 68
Ling, K., Hewitt, C., Tan, K.-L., Cheah, P.-S., Vidyadaran, S., Lai, M. I., Lee, H.-C., Simpson, K., Hyde, L., Pritchard, M. A., et al. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-624 · Cited by 68
“From the list of validated trisomic DEGs, Brwd1, Donson, Tmem50b and Itsn1 were upregulated in all brain regions, which concurs with previous studies [65-72].”
BackgroundResultGardiner, K. (2006) · Behavior Genetics · doi:10.1007/s10519-006-9051-1 · Cited by 69
The dark sides of amyloid in Alzheimer's disease pathogenesis
Sorrentino, P., Iuliano, A., Polverino, A., Jacini, F., & Sorrentino, G. (2014) · FEBS Letters · doi:10.1016/j.febslet.2013.12.038 · Cited by 64
Bartley, M. G., Marquardt, K., Kirchhof, D., Wilkins, H., Patterson, D. W., & Linseman, D. A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111172 · Cited by 61
“In addition, genetic reduction of AβPP from 3 copies to 2 copies improves endosomal pathology observed in the Ts65Dn mouse [27].”
Modulating lysosomal pH: a molecular and nanoscale materials design perspective
Zeng, J., Shirihai, O. S., & Grinstaff, M. W. (2020) · JoLS Journal of Life Sciences · doi:10.36069/jols/20201204 · Cited by 65
Blazek, J. D., Abeysekera, I., Li, J., & Roper, R. J. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv284 · Cited by 57
Presenilin/γ‐secretase activity regulates protein clearance from the endocytic recycling compartment
Zhang, M., Haapasalo, A., Kim, D. Y., Ingano, L. A. M., Pettingell, W. H., & Kovacs, D. M. (2006) · The FASEB Journal · doi:10.1096/fj.05-5531fje · Cited by 58
Early Endosome Morphology in Health and Disease
Kaur, G., & Lakkaraju, A. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-75402-4_41 · Cited by 56
“Similar endocytic defects are seen in a mouse model of Down’s syndrome (TS65Dn) (Cataldo et al. 2003), which replicates neurological symptoms seen in Down’s syndrome patients (Galdzicki and Siarey 2003).”
BackgroundNiederst, E. D., Reyna, S. M., & Goldstein, L. S. B. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-06-1049 · Cited by 51
“This is because there is considerable evidence that overexpression of APP can alter the sorting and trafficking of APP in neurons (Cataldo et al., 2003; Muresan and Muresan, 2007).”
BackgroundMouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities
Liu, C., Belichenko, P. V., Zhang, L., Fu, D., Kleschevnikov, A. M., Baldini, A., Antonarakis, S. E., Mobley, W. C., & Yu, Y. E. (2011) · Developmental Neuroscience · doi:10.1159/000329422 · Cited by 57
Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice
Stagni, F., Giacomini, A., Guidi, S., Ciani, E., Ragazzi, E., Filonzi, M., IASIO, R. D., Rimondini, R., & Bartesaghi, R. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.12.005 · Cited by 55
“The septal area is a brain region where Ts65Dn mice show endosome alterations starting from 2 months of age (Cataldo et al., 2003).”
BackgroundInfluentialMiranda, A. M., Herman, M., Cheng, R., Nahmani, E., Barrett, G., Micevska, E., Fontaine, G., Potier, M., Head, E., Schmitt, F. A., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.011 · Cited by 57
“Importantly though, overexpressing APP alone is not sufficient to alter endosomal size (Cataldo et al., 2003), and endosomal size is unaffected in APP microduplications (Cossec et al.”
BackgroundMini-review: Synaptojanin 1 and its implications in membrane trafficking
Choudhry, H. S., Aggarwal, M., & Pan, P. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.136288 · Cited by 54
“However, enlarged early endosomes were observed in multiple Synj1 overexpressing models [8,41,42].”
Mechanisms of AMPA Receptor Endosomal Sorting
Parkinson, G. T., & Hanley, J. G. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00440 · Cited by 57
The Therapeutic Potential of microRNAs in Nervous System Damage, Degeneration, and Repair
Hutchison, E. R., Okun, E., & Mattson, M. P. (2009) · NeuroMolecular Medicine · doi:10.1007/s12017-009-8086-x · Cited by 52
“Data from studies of trisomy 16 mice, a model of Down syndrome, suggest that increased APP expression is sufficient to cause neuropathological changes similar to those of AD (Cataldo et al., 2003; Salehi et al., 2006).”
Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome
D. Hamlett, E., A. Boger, H., Ledreux, A., M. Kelley, C., J. Mufson, E., F. Falangola, M., N. Guilfoyle, D., A. Nixon, R., Patterson, D., Duval, N., et al. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666150921095505 · Cited by 46
“APP overexpression, seen in Ts65Dn but not in Ts1Cje mice, is necessary to produce cholinergic cell loss [55] and DS-AD neuronal endosomal abnormalities seen at the earliest stage of disease [25, 56, 57] and during infancy long before disease hallmarks are present [57].”
BackgroundSelf-citationCatuara‐Solarz, S., Espinosa‐Carrasco, J., Erb, I., Langohr, K., Notredame, C., González, J. R., & Dierssen, M. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00330 · Cited by 47
Rafii, M. S., Kleschevnikov, A. M., Sawa, M., & Mobley, W. C. (2019) · Handbook of clinical neurology · doi:10.1016/b978-0-12-804766-8.00017-0 · Cited by 54
In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model
Chen, Y., Dyakin, V. V., Branch, C. A., Ardekani, B. A., Yang, D., Guilfoyle, D. N., Peterson, J. N., Peterhoff, C. M., Ginsberg, S. D., Cataldo, A. M., et al. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.026 · Cited by 50
Self-citationPopov, V. I., Kleschevnikov, A. M., Klimenko, O. A., Stewart, M. G., & Belichenko, P. V. (2010) · The Journal of Comparative Neurology · doi:10.1002/cne.22573 · Cited by 54
“The alternations of endosomes were previously reported in mouse models of DS, as well as in subjects with DS and Alzheimer’s disease (Cataldo et al., 1997, 2003).”
BackgroundKelley, C. M., Powers, B. E., Velázquez, R., Ash, J. A., Ginsberg, S. D., Strupp, B. J., & Mufson, E. J. (2013) · The Journal of Comparative Neurology · doi:10.1002/cne.23492 · Cited by 49
“This neuropathology is mirrored in the Ts65Dn mouse model of DS and AD (Holtzman et al., 1996; Granholm et al., 2000; Cooper et al., 2001; Hunter et al., 2003; Cataldo et al., 2003; Seo and Isacson, 2005; Contestabile et al., 2006).”
BackgroundLauritzen, I., Bécot, A., Bourgeois, A., Pardossi‐Piquard, R., Biferi, M. G., Barkats, M., & Checler, F. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0176-6 · Cited by 50
Cossec, J., Marquer, C., Panchal, M., Lazar, A. N., Duyckaerts, C. J., & Potier, M. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.03.010 · Cited by 47
Pousinha, P., Mouska, X., Raymond, E., Gwizdek, C., Dhib, G., Poupon, G., Zaragosi, L., Giudici, C., Bethus, I., Pacary, E., et al. (2017) · eLife · doi:10.7554/elife.25659 · Cited by 39
“This is observed in trisomy 21 (Down syndrome) in humans (McCarron et al., 2014), and trisomy 16 in mice (Cataldo et al., 2003), where an additional copy of the chromosome harboring APP is found.”
BackgroundTargeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits
Stringer, M., Goodlett, C. R., & Roper, R. J. (2017) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.334 · Cited by 45
“Therapeutics based on normalization of a single gene on an otherwise trisomic background to correct DS phenotypes is a significant paradigm shift, and has been supported by evidence from trisomic mouse models in which the normalization of one or two trisomic genes on an otherwise trisomic background from conception co…”
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
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