Increased App Expression in a Mouse Model of Down's Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration
| Autor: | Charles J. Epstein, Ryoko Takimoto-Kimura, Angela J. Villar, Weiming Xia, Pavel V. Belichenko, Bruce T. Lamb, Ralph A. Nixon, Ahmad Salehi, Gorazd B. Stokin, Janice S. Valletta, Lawrence S.B. Goldstein, Alexander M. Kleschevnikov, William A. Campbell, Kumar Sambamurti, Laura Shapiro Kulnane, William C. Mobley, Jean Dominique Delcroix, Peter Chung, Ke Zhan, Chengbiao Wu |
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| Jazyk: | angličtina |
| Předmět: |
medicine.medical_specialty
Neuroscience(all) HUMDISEASE Context (language use) Degeneration (medical) Biology MOLNEURO 03 medical and health sciences 0302 clinical medicine Internal medicine mental disorders medicine Amyloid precursor protein Cholinergic neuron 030304 developmental biology 0303 health sciences Basal forebrain General Neuroscience Neurodegeneration medicine.disease Endocrinology nervous system Axoplasmic transport biology.protein Cholinergic 030217 neurology & neurosurgery |
| Zdroj: | Neuron. (1):29-42 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2006.05.022 |
| Popis: | SummaryDegeneration 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. |
| Databáze: | OpenAIRE |
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