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 Lamb, Charles J. Epstein, Gorazd B. Stokin, Lawrence S B Goldstein, William C. Mobley

Research output: Contribution to journalArticle

355 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)29-42
Number of pages14
JournalNeuron
Volume51
Issue number1
DOIs
StatePublished - Jul 6 2006
Externally publishedYes

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Nerve Degeneration
Cholinergic Neurons
Nerve Growth Factor
Down Syndrome
Alzheimer Disease
Endosomes
Cholinergic Agents
Amyloid beta-Protein Precursor
Trisomy
Axons
Genes
Basal Forebrain

Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Salehi, A., Delcroix, J. D., Belichenko, P. V., Zhan, K., Wu, C., Valletta, J. S., ... 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

Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration. / Salehi, Ahmad; Delcroix, Jean Dominique; Belichenko, Pavel V.; Zhan, Ke; Wu, Chengbiao; Valletta, Janice S.; Takimoto-Kimura, Ryoko; Kleschevnikov, Alexander M.; Sambamurti, Kumar; Chung, Peter P.; Xia, Weiming; Villar, Angela; Campbell, William A.; Kulnane, Laura Shapiro; Nixon, Ralph A.; Lamb, Bruce; Epstein, Charles J.; Stokin, Gorazd B.; Goldstein, Lawrence S B; Mobley, William C.

In: Neuron, Vol. 51, No. 1, 06.07.2006, p. 29-42.

Research output: Contribution to journalArticle

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, B, 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
Salehi, Ahmad ; Delcroix, Jean Dominique ; Belichenko, Pavel V. ; Zhan, Ke ; Wu, Chengbiao ; Valletta, Janice S. ; Takimoto-Kimura, Ryoko ; Kleschevnikov, Alexander M. ; Sambamurti, Kumar ; Chung, Peter P. ; Xia, Weiming ; Villar, Angela ; Campbell, William A. ; Kulnane, Laura Shapiro ; Nixon, Ralph A. ; Lamb, Bruce ; Epstein, Charles J. ; Stokin, Gorazd B. ; Goldstein, Lawrence S B ; Mobley, William C. / Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration. In: Neuron. 2006 ; Vol. 51, No. 1. pp. 29-42.
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