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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Written from the paper’s full text.
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.
Model-written summary. Check it against the paper before relying on it.
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Cites
Statistics
Claims the paper makes
8 of 22 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured
- Findingcitation
These same populations of basal forebrain neurons typically develop less severe atrophy in Ts1Cje and Ts65Dn-App+/+/− mice or older ages compared with age-matched Ts65Dn mice.
“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.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Sago et al., 1998 source
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)
Experimental — accuracy not yet measured
- Premisecitation
Ts65Dn mice do not deposit β-amyloid.
“Unlike what occurs in human disorders, however, Ts65Dn mice do not deposit -amyloid.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Holtzman et al., 1996 source
- Premisecitation
Basal forebrain neurons in Ts65Dn mice later develop aging-related atrophy and degenerative changes, as in AD and DS.
“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).”
Quote in the paperSubstantial claim2 of 2 sources checked - Findingown data
Ts1Cje and Ts65Dn-App+/+/− mice, which have two copies of App, showed normal endosomal morphology in the basal forebrain in contrast to Ts65Dn mice.
“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.”
Quote in the paperSubstantial claim - Findingown data
Rab4 immunoreactivity was principally associated with small vesicular profiles consistent with the size and location of recycling vesicles.
“Rab4 immunoreactivity was principally associated with small vesicular profiles consistent with the size and location of recycling vesicles.”
Quote in the paperNot a substantial claim
- Findingown data
Ts1Cje and Ts65Dn-App+/+/− mice displayed early endosomes of normal size in the MSN, NBM, neocortex, and hippocampus in numbers qualitatively similar to 2N brains.
“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).”
Quote in the paperSubstantial claim - Findingown data
A compensatory rise in levels of the GTPase rab4 was detected in the same neuronal groups in Ts65Dn mice.
“A compensatory rise in levels of the GTPase rab4, which stimulates endosome recycling to the plasmalemma, was also detected in the same neuronal groups.”
Quote in the paperNot a substantial claim - Findingown data
By 6 months of age, swollen, rab5-positive endosomes were present in most basal forebrain neurons of the MSN as well as the NBM in Ts65Dn mice.
“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.”
Quote in the paperSubstantial claim - Findingown data
Ts65Dn mice show increased immunoreactivity for the endosome recycling marker rab4 in neurons.
“Western blot analysis, which revealed a 2.5-fold increase in rab4 levels ( p Ͻ 0.0006; n ϭ 4).”
Quote in the paperSubstantial claim - Findingown data
Overexpressing App at high levels in mice did not alter early endosomes.
“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.”
Quote in the paperSubstantial claim - Findingown data
Both Ts65Dn-App+/+/− and Ts1Cje mice expressed rab4 immunoreactivity at levels similar to those in neurons from age-matched littermate controls.
“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.”
Quote in the paperSubstantial claim - Findingown data
Transgenic mice overexpressing the Swedish mutation of human APP751 alone or with the London mutation had normal-appearing rab5-positive early endosomes and patterns of EEA1, rab4, and rabaptin5 similar to 2N controls.
“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.”
Quote in the paperSubstantial claim - Findingown data
Ts65Dn mice develop enlarged neuronal early endosomes similar to those in AD and DS individuals.
“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.”
Quote in the paperSubstantial claim - Findingown data
Early endosomes in the same neuronal populations appeared as typical, small, uniform vesicular compartments in 2N littermate control mice.
“Early endosomes in the same neuronal populations appeared as the typical, small, and uniform vesicular compartments in 2N littermate control mice (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
Endosomal enlargement was detected in fewer neurons within the amygdala, cingulate cortex, and hippocampus from Ts65Dn mice.
“Endosomal enlargement was detected in fewer neurons within the amygdala, cingulate cortex, and hippocampus from Ts65Dn mice.”
Quote in the paperSubstantial claim - Findingown data
Intraneuronal Aβ is present within rab5-positive vesicular compartments of neurons from Ts65Dn mice.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
Ts65Dn mice develop neuronal endosome abnormalities strongly resembling the highly AD-specific endocytic alterations that develop at the earliest stages of AD.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
Endosomal dysfunction has pathogenic significance in AD.
“and further establish the pathogenic significance of endosomal dysfunction in AD.”
Quote in the paperSubstantial claim - Premisecitation
Ts65Dn mice with a segmental trisomy extending from App to Mx1 exhibit behavioral and cognitive abnormalities not unlike some abnormalities seen in individuals with DS.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Reeves et al., 1995 source
- Premisecitation
Early endosomal alterations are the earliest known pathology in sporadic AD and DS.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Similar endosomal abnormalities, when modeled in cells, are associated with increased Aβ production.
“Similar endosomal abnormalities, when modeled in cells, are associated with increased A production (Grbovic et al., 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Grbovic et al., 2002
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
One or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype.
“implying that one or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype.”
Quote in the paperSubstantial claim - Interpretationreasoning
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.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
Functionally, endosomal uptake and fusion were increased in Ts65Dn neurons.
“implying that functionally, endosomal uptake and fusion were increased.”
Quote in the paperSubstantial claim - Premisecitation
Endosomal alterations in AD and DS develop in otherwise normal-appearing neurons of regions that become the most severely affected in the disease, including hippocampus, neocortex, and basal forebrain.
“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.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Cataldo et al., 1997 source
- cites Cataldo et al., 2000a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The development of early endosomal abnormalities in Ts65Dn mice is dependent on App gene triplication.
“We have shown that the development of early endosomal abnormalities in Ts65Dn mice is dependent on App gene triplication.”
Quote in the paperSubstantial claim - Interpretationown data
App gene triplication is essential for causing AD-related endosomal abnormalities.
“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.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- Classified as probably not a substantial claim. 3
- The quote only partly states this claim. 2
May combine two claims.
PremisecitationTs1Cje mice do not develop BFCN atrophy and degeneration, and they have less severe learning and behavioral deficits than Ts65Dn mice.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Sago et al., 1998 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA twofold overexpression of 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.
“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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Sturchler-Pierrat et al., 1997 source
May combine two claims.
PremisecitationThe ApoE gene is associated with increased risk of AD and is not located on the triplicated segment of MMU16, but it is overexpressed to higher levels in Ts65Dn mice than predicted on the basis of gene dosage.
“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).”
Quote in the paperNot a substantial claim1 of 2 sources checkedMay combine two claims.
PremisecitationTs65Dn and Ts1Cje mice survive to adulthood and exhibit morphological, biochemical, and transcriptional changes seen in human DS.
“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).”
Quote in the paperSubstantial claim1 of 3 sources checkedMay combine two claims.
Findingown dataNot all neuronal populations in Ts65Dn mice exhibited enlarged endosomes; neurons in the caudate nucleus and putamen or in cerebellar Purkinje cells displayed normal-sized early endosomes.
“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.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataTs65Dn mice show increased immunoreactivity for markers of endosome fusion (rab5, EEA1, rabaptin5) in neurons.
“the levels of rabaptin5 and EEA1 immunoreactivities were higher in Ts65Dn mice than in age-matched littermate controls (Fig. 2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSelectively deleting one copy of App or a small portion of the chromosome 16 segment containing App from Ts65Dn mice eliminated the endosomal phenotype.
“Selectively deleting one copy of App or a small portion of the chromosome 16 segment containing App from Ts65Dn mice eliminated the endosomal phenotype.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe numbers of neurons 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 young, 2-month-old mice.
“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.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataThe endosomal abnormalities in Ts65Dn mice are most prominent in neurons of the basal forebrain.
“In young Ts65Dn mice, these enlarged endosomes were prominent in a majority of the neurons in the MSN of the basal forebrain.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningFindings 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.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationImmunocytochemical studies of brain tissue from DS subjects have shown a direct correlation between elevated BACE-2 in brain and AD-like neuropathology.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Motonaga et al., 2002 source
May combine two claims.
PremisecitationEndosomal abnormalities in AD are influenced by ApoE genotype and do not develop in familial AD caused by presenilin mutations.
“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.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe ApoE4 allele accelerates the onset of endosome pathology in AD.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Corder et al., 1993 source
May combine two claims.
InterpretationcitationEndosomal abnormalities are AD subtype-specific and are not a response to amyloid deposition.
“underscoring that they are AD subtype-specific and are also not a response to amyloid deposition.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIncreased App gene dosage is necessary but not sufficient for endosome pathology to develop in Ts65Dn mice.
“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.”
Quote in the paperSubstantial claim
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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 · see citing works
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 · see citing works
“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. J., Potier, M., & Delatour, B. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0312-8 · Cited by 441 · see citing works
“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 377 · see citing works
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 371 · see citing works
“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-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 · see citing works
“The appearance of these abnormalities is promoted by APOE4 [4] and, in a mouse model of Down syndrome, requires App triplication [5].”
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 · see citing works
Self-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 288 · see citing works
“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 291 · see citing works
“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 · see citing works
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 281 · see citing works
“…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 · see citing works
“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 256 · see citing works
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 · see citing works
“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 238 · see citing works
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 227 · see citing works
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 · see citing works
“[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 210 · see citing works
“…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 208 · see citing works
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 · see citing works
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 · see citing works
“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., Weissmiller, A. M., White, J. A., Fang, F., Wang, X., Wu, Y.-W., Pearn, M. L., Zhao, X.-B., Sawa, M., Chen, S.-D., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci82409 · Cited by 157 · see citing works
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 180 · see citing works
“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 168 · see citing works
“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 · see citing works
“…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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 154 · see citing works
“…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 · see citing works
Down syndrome: searching for the genetic culprits
Lana-Elola, E., Watson-Scales, S., Fisher, E., & Tybulewicz, V. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.008078 · Cited by 149 · see citing works
“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 · see citing works
“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 139 · see citing works
“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 136 · see citing works
“, 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 135 · see citing works
“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 · see citing works
“, 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 133 · see citing works
“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 128 · see citing works
Self-citationDysregulation of protein trafficking in neurodegeneration
Wang, X., Huang, T. Y., Bu, G., & Xu, H. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-31 · Cited by 124 · see citing works
“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 · see citing works
“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 123 · see citing works
“, 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 · see citing works
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 · see citing works
“, 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 112 · see citing works
Mrak, R. E., & Griffin, W. S. T. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.7.679 · Cited by 108 · see citing works
“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 · see citing works
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 · see citing works
“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 105 · see citing works
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 102 · see citing works
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 100 · see citing works
“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 100 · see citing works
Jiang, Y., Rigoglioso, A., Peterhoff, C., Pawlik, M., Sato, Y., Bleiwas, C., Stavrides, P. H., Smiley, J., Ginsberg, S. D., Mathews, P., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.11.013 · Cited by 92 · see citing works
“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 · see citing works
“…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 83 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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., & Levy, E. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01347 · Cited by 73 · see citing works
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 74 · see citing works
“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 71 · see citing works
“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 74 · see citing works
“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 73 · see citing works
Mohajer, G., Lee, E. S., & Bae, Y. H. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9277-5 · Cited by 73 · see citing works
“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 71 · see citing works
“, 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 · see citing works
“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., Fang, F., Ding, J.-Q., & Wu, C.-B. (2018) · Traffic : the International Journal of Intracellular Transport · doi:10.1111/tra.12547 · Cited by 70 · see citing works
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 · see citing works
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 · see citing works
Self-citationChen, X., Sawa, M., & Mobley, W. C. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.341 · Cited by 65 · see citing works
“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 · see citing works
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 64 · see citing works
“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 63 · see citing works
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 66 · see citing works
“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 63 · see citing works
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 · see citing works
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 · see citing works
“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 60 · see citing works
Blazek, J. D., Abeysekera, I., Li, J., & Roper, R. J. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv284 · Cited by 54 · see citing works
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 57 · see citing works
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 · see citing works
“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 · see citing works
“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 55 · see citing works
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 53 · see citing works
“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 55 · see citing works
“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 · see citing works
“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 53 · see citing works
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 51 · see citing works
“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
Hamlett, E. D., Boger, H. A., Ledreux, A., Kelley, C. M., Mufson, E. J., Falangola, M. F., Guilfoyle, D. N., Nixon, R. A., Patterson, D., Duval, N., et al. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666150921095505 · Cited by 51 · see citing works
“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 44 · see citing works
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 52 · see citing works
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 49 · see citing works
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 48 · see citing works
“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 48 · see citing works
“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., Barkats, M., & Checler, F. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0176-6 · Cited by 37 · see citing works
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 46 · see citing works
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 · see citing works
“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 44 · see citing works
“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…”
BackgroundRen, R., Zhang, Y., Dammer, E. B., Zhou, Y., Wang, L., Liu, X., Feng, B.-L., Jiang, G., Chen, S., Wang, G., et al. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9484-8 · Cited by 45 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.
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