Cited by 543Alzheimer's disease research and treatmentsDown syndrome and intellectual disability researchNerve injury and regeneration

Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration

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Salehi, Ahmad, Delcroix, Jean-Dominique, Belichenko, Pavel V., Zhan, Ke, Wu, Chengbiao, Valletta, Janice S., Takimoto-Kimura, Ryoko, Kleschevnikov, Alexander M. +12 more·2006·Neuron

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.

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Crossref · 10.1016/j.neuron.2006.05.022

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Authors
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.
Affiliations
  • Stanford University (US)
  • Medical University of South Carolina (US)
  • Harvard University (US)
  • University of California, San Francisco (US)
  • Case Western Reserve University (US)
  • Nathan Kline Institute for Psychiatric Research (US)
  • University of California San Diego (US)
  • Stanford Medicine (US)
Corresponding author
Salehi, Ahmad
Venue
Neuron
Publisher
Elsevier BV
Published
2006-07
Volume
51
Issue
1
Pages
29-42
ISSN
0896-6273 (ISSN-L)
OpenAlex
W2073374252
Cited by
543
References
69
Citations by year
2026: 9 · 2025: 18 · 2024: 13 · 2023: 19 · 2022: 27 · 2021: 23 · 2020: 24 · 2019: 21 · 2018: 25 · 2017: 23 · 2016: 33 · 2015: 28 · 2014: 35 · 2013: 33 · 2012: 27
FWCI
26.14
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Public Health Service (31498)
  • National Institute on Aging (R01AG016999, AG 16999)
  • National Institute of Neurological Disorders and Stroke (NS 38869, R01NS038869)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords
Down syndrome, amyloid precursor protein, nerve growth factor, retrograde transport, cholinergic neurons, basal forebrain, neurodegeneration, Ts65Dn mouse model, early endosomes, Alzheimer's disease, APP mutations
MeSH terms
Alzheimer Disease, Animals, Axonal Transport, Cholinergic Fibers, Disease Models, Animal, Down Syndrome, Female, Humans, Male, Mice, Transgenic, Nerve Degeneration, Endosomes, Up-Regulation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Knockout, Basal Nucleus of Meynert, Nerve Growth Factor, Protein Transport, Mice, Plaque, Amyloid

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