Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.
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.
Salehi
Ahmad
A
Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA. asalehi@stanford.edu
Delcroix
Jean-Dominique
JD
Belichenko
Pavel V
PV
Zhan
Ke
K
Wu
Chengbiao
C
Valletta
Janice S
JS
Takimoto-Kimura
Ryoko
R
Kleschevnikov
Alexander M
AM
Sambamurti
Kumar
K
Chung
Peter P
PP
Xia
Weiming
W
Villar
Angela
A
Campbell
William A
WA
Kulnane
Laura Shapiro
LS
Nixon
Ralph A
RA
Lamb
Bruce T
BT
Epstein
Charles J
CJ
Stokin
Gorazd B
GB
Goldstein
Lawrence S B
LS
Mobley
William C
WC
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics; D020532:Basal Nucleus of Meynert / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002799:Cholinergic Fibers / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020932:Nerve Growth Factor