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.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA. asalehi@stanford.edu
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salehi
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Delcroix
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Belichenko
authors.forename: Ke
authors.initials: K
authors.lastname: Zhan
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
authors.forename: Janice S
authors.initials: JS
authors.lastname: Valletta
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takimoto-Kimura
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kleschevnikov
authors.forename: Kumar
authors.initials: K
authors.lastname: Sambamurti
authors.forename: Peter P
authors.initials: PP
authors.lastname: Chung
authors.forename: Weiming
authors.initials: W
authors.lastname: Xia
authors.forename: Angela
authors.initials: A
authors.lastname: Villar
authors.forename: William A
authors.initials: WA
authors.lastname: Campbell
authors.forename: Laura Shapiro
authors.initials: LS
authors.lastname: Kulnane
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Gorazd B
authors.initials: GB
authors.lastname: Stokin
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020932:Nerve Growth Factor