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Reorganization of Cholinergic Terminals in the Cerebral Cortex and Hippocampus in Transgenic Mice Carrying Mutated Presenilin-1 and Amyloid Precursor Protein Transgenes
Open accessAbstract
Cholinergic deficits are one of the most consistent neuropathological landmarks in Alzheimer’s disease (AD). We have examined transgenic mouse models (PS1 M146L, APP K670N,M671L) and a doubly transgenic line (APP K670N,M671L+ PS1 M146L) that overexpress mutated AD-related genes [presenilin-1 (PS1) and the amyloid precursor protein (APP)] to investigate the effect of AD-related gene overexpression and/or amyloidosis on cholinergic parameters. The size of the basal forebrain cholinergic neurons and the pattern of cholinergic synapses in the hippocampus and cerebral cortex were revealed by immunohistochemical staining for choline acetyltransferase and the vesicular acetylcholine transporter, respectively. At the time point studied (8 months), no apparent changes in either the size or density of cholinergic synapses were found in the PS1 M146L mutant relative to the nontransgenic controls. However, the APP K670N,M671L mutant showed a significant elevation in the density of cholinergic synapses in the frontal and parietal cortices. Most importantly, the double mutant (APP K670N,M671L+ PS1 M146L), which had extensive amyloidosis, demonstrated a prominent diminution in the density of cholinergic synapses in the frontal cortex and a reduction in the size of these synapses in the frontal cortex and hippocampus. Nonetheless, no significant changes in the size of basal forebrain cholinergic neurons were observed in these three mutants. This study shows a novel role of APP and a synergistic effect of APP and PS1 that correlates with amyloid load on the reorganization of the cholinergic network in the cerebral cortex and hippocampus at the time point studied.
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“Similarly, the density of cortical cholinergic synapses has been shown to increase in mice overexpressing FAD mutant APP and decreased in mice expressing FAD mutant APP combined with FAD mutant PS1 (52).”
From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [52]
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Metadata
- Authors
- Wong, T. P., Debeir, T., Duff, K., & Cuello, A. C.
- Affiliations
- McGill University (CA)
- Nathan Kline Institute for Psychiatric Research (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1999-04-01
- Volume
- 19
- Issue
- 7
- Pages
- 2706-2716
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6786057
- OpenAlex
- W1869587992
- Cited by
- 196
- References
- 59
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 5 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 2 · 2012: 4
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Minnesota
- Croucher Foundation
- National Institutes of Health (5r01ag011903-03)
- Medical Research Council
- National Institute on Aging (AG-11903, AG 146133)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cholinergic synapses, presenilin 1, amyloid precursor protein, amyloidosis, choline acetyltransferase, vesicular acetylcholine transporter, basal forebrain cholinergic neurons, cerebral cortex, hippocampus, synaptic density, transgenic mouse model
- MeSH terms
- Acetylcholine, Alzheimer Disease, Analysis of Variance, Animals, Cerebral Cortex, Hippocampus, Membrane Proteins, Mice, Transgenic, Mutation, Nerve Endings, Synapses, Up-Regulation, Prosencephalon, Amyloid beta-Protein Precursor, Entorhinal Cortex, Mice, Presenilin-1
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