Conditional Inactivation of Presenilin 1 Prevents Amyloid Accumulation and Temporarily Rescues Contextual and Spatial Working Memory Impairments in Amyloid Precursor Protein Transgenic Mice
Open accessAbstract
Accumulation of β-amyloid (Aβ) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's disease (AD). Presenilin 1 (PS1) plays an essential role in the γ-secretase cleavage of the amyloid precursor protein (APP) and the generation of Aβ peptides. Reduction of Aβ generation via the inhibition of γ-secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out ( PS1 cKO) mice can prevent the accumulation of Aβ peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice ( PS1 cKO; APP Tg) effectively prevented the accumulation of Aβ peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO; APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO; APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of Aβ via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.
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PS1 conditional knockout mice show aberrant accumulation of APP βCTFs in distal axons/pre-synaptic compartments and some in distal dendrites/post-synaptic compartments.
“Indirect support for synapse-specific Aβ generation also comes from PS1 conditional knockout mice, which showed aberrant accumulation of APP βCTFs in distal axons/pre-synaptic compartments [162] and also some anatomically selective accumulation in distal dendrites/post-synaptic compartments (personal observations).”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [162]
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- Authors
- Saura, C. A., Chen, G., Malkani, S., Choi, S.-Y., Takahashi, R. H., Zhang, D., Gouras, G. K., Kirkwood, A., Morris, R. G. M., & Shen, J.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Edinburgh (GB)
- Johns Hopkins University (US)
- Cornell University (US)
- Corresponding author
- Shen, Jie
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-07-20
- Volume
- 25
- Issue
- 29
- Pages
- 6755-6764
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725351
- OpenAlex
- W2164975702
- Cited by
- 157
- References
- 61
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 11 · 2015: 7 · 2014: 19 · 2013: 10 · 2012: 7
- FWCI
- 7.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Alzheimer's Association
- Alzheimer's Research Trust
- Medical Research Council
- National Institute of Neurological Disorders and Stroke (RF1NS041783, R01NS041783)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- presenilin 1, conditional knockout mice, amyloid precursor protein, amyloid-beta deposition, gamma-secretase inhibition, Alzheimer's disease, amyloid plaques, contextual fear conditioning, spatial working memory, APP C-terminal fragments, neuroinflammation, APP transgenic mice
- MeSH terms
- Aging, Alzheimer Disease, Amyloidosis, Animals, Behavior, Animal, Membrane Proteins, Memory Disorders, Memory, Short-Term, Mice, Transgenic, Neuronal Plasticity, Endopeptidases, Space Perception, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Presynaptic Terminals, Mice, Knockout, Maze Learning, Mice, Presenilin-1, Amyloid Precursor Protein Secretases
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