Cholinergic neurodegeneration in an Alzheimer mouse model overexpressing amyloid-precursor protein with the Swedish-Dutch-Iowa mutations
Open accessAbstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is mainly characterized by beta-amyloid (Aβ) plaque deposition, Tau pathology and dysfunction of the cholinergic system causing memory impairment. The aim of the present study was to examine (1) anxiety and cognition, (2) Aβ plaque deposition and (3) degeneration of cholinergic neurons in the nucleus basalis of Meynert (nbM) and cortical cholinergic innervation in an Alzheimer mouse model (APP_SweDI; overexpressing amyloid precursor protein (APP) with the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations). Our results show that 12-month-old APP_SweDI mice were more anxious and had more memory impairment. A large number of Aβ plaques were already visible at the age of 6 months and increased with age. A significant decrease in cholinergic neurons was seen in the transgenic mouse model in comparison to the wild-type mice, identified by immunohistochemistry against choline acetyltransferase (ChAT) and p75 neurotrophin receptor as well as by in situ hybridization. Moreover, a significant decrease in cortical cholinergic fiber density was found in the transgenic mice as compared to the wild-type. In the cerebral cortex of APP_SweDI mice, swollen cholinergic varicosities were seen in the vicinity of Aβ plaques. In conclusion, the present study shows that in an AD mouse model (APP_SweDI mice) a high Aβ plaque load in the cortex causes damage to cholinergic axons in the cortex, followed by subsequent retrograde-induced cell death of cholinergic neurons and some forms of compensatory processes. This degeneration was accompanied by enhanced anxiety and impaired cognition.
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In 12-month-old TgSweDI mice, a significant decrease in the number of cholinergic neurons was reported in the nucleus basalis of Meynert compared to age-matched WT animals, together with a reduction in cholinergic fiber density.
“Quantifications of neurons stained with choline acetyltransferase (ChAT) in the nucleus basalis of Meynert (nbM) revealed a significant decrease compared to age-matched WT animals, together with a reduction in cholinergic fiber density [44].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [44]
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- Authors
- Foidl, B. M., Do-Dinh, P., Hutter-Schmid, B., Bliem, H. R., & Humpel, C.
- Affiliations
- Innsbruck Medical University (AT)
- Corresponding author
- Humpel, Christian
- ORCID
- Humpel, Christian
- Venue
- Neurobiology of Learning and Memory
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 136
- Pages
- 86-96
- ISSN
- 1074-7427 (ISSN-L)
- PMC
- PMC6020032
- OpenAlex
- W2521088506
- Cited by
- 24
- References
- 45
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 4
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neurobiology of Learning and Memory (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Austrian Science Fund (P24734-B24)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cholinergic neurodegeneration, amyloid plaques, nucleus basalis of Meynert, anxiety, memory impairment, choline acetyltransferase, p75 neurotrophin receptor, APP overexpression
- MeSH terms
- Alzheimer Disease, Animals, Anxiety, Behavior, Animal, Cerebral Cortex, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Protein Precursor, Basal Nucleus of Meynert, Mice, Plaque, Amyloid, Cholinergic Neurons
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