Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration
Open accessAbstract
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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Overexpression of WT APP or APP bearing FAD mutations in Drosophila and mice can cause impaired axonal transport and axonal defects.
“Intriguingly, recent work revealed that overexpression of WT APP or APP bearing FAD mutations in Drosophila and mice can cause impaired axonal transport and axonal defects (7,8,29,30).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [8]
Human Ab40 or Ab42 peptides are not needed to generate NGF transport deficits.
“and that human Ab40 or Ab42 peptides are not needed to generate NGF transport deficits”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [8]
Increasing human Ab42 levels may minimally enhance NGF transport deficits caused by APP overexpression.
“although increasing human Ab42 levels may minimally enhance NGF transport deficits caused by APP overexpression.”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [8]
NGF transport deficits can be caused by overexpression of APP.
“The results suggest that NGF transport deficits can be caused by overexpression of APP”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [8]
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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
- ORCID
- 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
- bronze
- doi.org
- Licence
- 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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