Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration

Ahmad Salehi; Jean Dominique Delcroix; Pavel V. Belichenko; Ke Zhan; Chengbiao Wu; Janice S. Valletta; Ryoko Takimoto-Kimura; Alexander M. Kleschevnikov; Kumar Sambamurti; Peter P. Chung; Weiming Xia; Angela Villar; William A. Campbell; Laura Shapiro Kulnane; Ralph A. Nixon; Bruce T. Lamb; Charles J. Epstein; Gorazd B. Stokin; Lawrence S.B. Goldstein; William C. Mobley

doi:10.1016/j.neuron.2006.05.022

Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration

Ahmad Salehi, Jean Dominique Delcroix, Pavel V. Belichenko, Ke Zhan, Chengbiao Wu, Janice S. Valletta, Ryoko Takimoto-Kimura, Alexander M. Kleschevnikov, Kumar Sambamurti, Peter P. Chung, Weiming Xia, Angela Villar, William A. Campbell, Laura Shapiro Kulnane, Ralph A. Nixon, Bruce T. Lamb, Charles J. Epstein, Gorazd B. Stokin, Lawrence S.B. Goldstein, William C. Mobley

Houston Methodist

Research output: Contribution to journal › Article › peer-review

452 Scopus citations

Abstract

Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.

Original language	English (US)
Pages (from-to)	29-42
Number of pages	14
Journal	Neuron
Volume	51
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2006.05.022
State	Published - Jul 6 2006

Keywords

HUMDISEASE
MOLNEURO

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/j.neuron.2006.05.022

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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., Xia, W., Villar, A., Campbell, W. A., Kulnane, L. S., Nixon, R. A., Lamb, B. T., Epstein, C. J., Stokin, G. B., Goldstein, L. S. B., & Mobley, W. C. (2006). Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration. Neuron, 51(1), 29-42. https://doi.org/10.1016/j.neuron.2006.05.022

Salehi, A, Delcroix, JD, Belichenko, PV, Zhan, K, Wu, C, Valletta, JS, Takimoto-Kimura, R, Kleschevnikov, AM, Sambamurti, K, Chung, PP, Xia, W, Villar, A, Campbell, WA, Kulnane, LS, Nixon, RA, Lamb, BT, Epstein, CJ, Stokin, GB, Goldstein, LSB & Mobley, WC 2006, 'Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration', Neuron, vol. 51, no. 1, pp. 29-42. https://doi.org/10.1016/j.neuron.2006.05.022

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title = "Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration",

abstract = "Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.",

keywords = "HUMDISEASE, MOLNEURO",

author = "Ahmad Salehi and Delcroix, {Jean Dominique} and Belichenko, {Pavel V.} and Ke Zhan and Chengbiao Wu and Valletta, {Janice S.} and Ryoko Takimoto-Kimura and Kleschevnikov, {Alexander M.} and Kumar Sambamurti and Chung, {Peter P.} and Weiming Xia and Angela Villar and Campbell, {William A.} and Kulnane, {Laura Shapiro} and Nixon, {Ralph A.} and Lamb, {Bruce T.} and Epstein, {Charles J.} and Stokin, {Gorazd B.} and Goldstein, {Lawrence S.B.} and Mobley, {William C.}",

note = "Funding Information: This research was sponsored by grants from the NIA (AG16999, W.C.M.), NINDS (NS38869, W.C.M.), NICHD (31498, C.J.E.), Adler Foundation (J.D.D.), Alzheimer Association and State of California Alzheimer's Program (A.S. and W.C.M.), McGowan Charitable Trust, Larry L. Hillblom Foundation, and the Down Syndrome Research and Treatment Foundation (W.C.M.). ",

year = "2006",

month = jul,

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doi = "10.1016/j.neuron.2006.05.022",

language = "English (US)",

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T1 - Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration

AU - Salehi, Ahmad

AU - Delcroix, Jean Dominique

AU - Belichenko, Pavel V.

AU - Zhan, Ke

AU - Wu, Chengbiao

AU - Valletta, Janice S.

AU - Takimoto-Kimura, Ryoko

AU - Kleschevnikov, Alexander M.

AU - Sambamurti, Kumar

AU - Chung, Peter P.

AU - Xia, Weiming

AU - Villar, Angela

AU - Campbell, William A.

AU - Kulnane, Laura Shapiro

AU - Nixon, Ralph A.

AU - Lamb, Bruce T.

AU - Epstein, Charles J.

AU - Stokin, Gorazd B.

AU - Goldstein, Lawrence S.B.

AU - Mobley, William C.

N1 - Funding Information: This research was sponsored by grants from the NIA (AG16999, W.C.M.), NINDS (NS38869, W.C.M.), NICHD (31498, C.J.E.), Adler Foundation (J.D.D.), Alzheimer Association and State of California Alzheimer's Program (A.S. and W.C.M.), McGowan Charitable Trust, Larry L. Hillblom Foundation, and the Down Syndrome Research and Treatment Foundation (W.C.M.).

PY - 2006/7/6

Y1 - 2006/7/6

N2 - Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.

AB - Degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive dysfunction in Alzheimer's disease (AD) and Down's syndrome (DS). We used Ts65Dn and Ts1Cje mouse models of DS to show that the increased dose of the amyloid precursor protein gene, App, acts to markedly decrease NGF retrograde transport and cause degeneration of BFCNs. NGF transport was also decreased in mice expressing wild-type human APP or a familial AD-linked mutant APP; while significant, the decreases were less marked and there was no evident degeneration of BFCNs. Because of evidence suggesting that the NGF transport defect was intra-axonal, we explored within cholinergic axons the status of early endosomes (EEs). NGF-containing EEs were enlarged in Ts65Dn mice and their App content was increased. Our study thus provides evidence for a pathogenic mechanism for DS in which increased expression of App, in the context of trisomy, causes abnormal transport of NGF and cholinergic neurodegeneration.

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KW - MOLNEURO

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VL - 51

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JO - Neuron

JF - Neuron

IS - 1

ER -

Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration

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