Failed retrograde transport of NGF in a mouse model of Down's syndrome: Reversal of cholinergic neurodegenerative phenotypes following NGF infusion
Open accessAbstract
Age-related degeneration of basal forebrain cholinergic neurons (BFCNs) contributes to cognitive decline in Alzheimer's disease and Down's syndrome. With aging, the partial trisomy 16 (Ts65Dn) mouse model of Down's syndrome exhibited reductions in BFCN size and number and regressive changes in the hippocampal terminal fields of these neurons with respect to diploid controls. The changes were associated with significantly impaired retrograde transport of nerve growth factor (NGF) from the hippocampus to the basal forebrain. Intracerebroventricular NGF infusion reversed well established abnormalities in BFCN size and number and restored the deficit in cholinergic innervation. The findings are evidence that even BFCNs chronically deprived of endogenous NGF respond to an intervention that compensates for defective retrograde transport. We suggest that age-related cholinergic neurodegeneration may be a treatable disorder of failed retrograde NGF signaling.
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Basal forebrain neurons in Ts65Dn mice later develop aging-related atrophy and degenerative changes, as in AD and DS.
“Ts65Dn mice also exhibit age-related atrophy and neurodegeneration of basal forebrain cholinergic neurons (BFCNs) and extensive astrocytic hypertrophy resembling these aspects of the neuropathology in AD and DS (Holtzman et al., 1996;Cooper et al., 2001).”
From <i>App</i>Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome (2003) · cites this paper as Cooper et al., 2001
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- Authors
- Cooper, J. D., Salehi, A., Delcroix, J.-D., Howe, C. L., Belichenko, P. V., Chua-Couzens, J., Kilbridge, J. F., Carlson, E. J., Epstein, C. J., & Mobley, W. C.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-08-14
- Volume
- 98
- Issue
- 18
- Pages
- 10439-10444
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC56979
- OpenAlex
- W2146113273
- Cited by
- 336
- References
- 3
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 6 · 2023: 3 · 2022: 12 · 2021: 18 · 2020: 2 · 2019: 7 · 2018: 8 · 2017: 8 · 2016: 13 · 2015: 17 · 2014: 12 · 2013: 12 · 2012: 19
- FWCI
- 10.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (5r01hd031498-05)
- National Institute on Aging (R01AG016999, AG 16999)
- National Institute of Neurological Disorders and Stroke (NS 38869, R01NS038869)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-31498)
- 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
- nerve growth factor, retrograde transport, Down syndrome, Ts65Dn mouse model, basal forebrain cholinergic neurons, cholinergic neurodegeneration, trisomy 16, Alzheimer's disease, cognitive decline, neurotrophic signaling
- MeSH terms
- Aging, Animals, Biological Transport, Active, Cell Count, Cells, Cholinergic Fibers, Disease Models, Animal, Down Syndrome, Hippocampus, Humans, Infusions, Parenteral, Mice, Mutant Strains, Nerve Degeneration, Phenotype, Trisomy, Prosencephalon, Nerve Growth Factor, Mice
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