Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia
Open accessAbstract
Background: A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-β precursor protein (APP) processing, which is genetically linked to Alzheimer’s disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDD KI). β-cleavage of APP yields the β-carboxyl-terminal (β-CTF) and the amino-terminal-soluble APPβ (sAPPβ) fragments. γ-secretase processing of β-CTF generates Aβ, which is considered the main cause of AD. However, inhibiting Aβ production did not rescue the deficits of FDD KI mice, suggesting that sAPPβ/β-CTF, and not Aβ, are the toxic species causing memory loss. Results: Here, we have further analyzed the effect of γ-secretase inhibition. We show that treatment with a γ-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDD KI mice. This deleterious effect on memory correlates with increased levels of the β/α-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDD KI mice, which is consistent with inhibition of γ-secretase activity. Conclusion: This harmful effect of the GSI is in sharp contrast with a pathogenic role for Aβ, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic β/α-CTFs caused by GSI treatment. However, γ-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other γ-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting γ-secretase in the therapy of AD. Overall, the data also indicate that FDD KI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.
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The accumulation of β-secretase cleaved fragments of APP has been implicated as mediators of behavioral dysfunction.
“The accumulation of β-secretase cleaved fragments of APP has been implicated as mediators of behavioral dysfunction”
From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [55]
Previous studies have shown that aggregated Aβ can interact with APP.
“and previous studies have shown that aggregated Aβ can interact with APP [54-56]”
From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [55]
The Background states that Aβ is derived from APP and that BRI2 binds APP, but it does not say that aggregated Aβ interacts with APP. Searches for aggregated Aβ binding or interacting with APP found no passage addressing that interaction in our copy. (LLM, conf=0.73)
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- Authors
- Tamayev, R., & D’Adamio, L.
- Affiliations
- Albert Einstein College of Medicine (US)
- Venue
- Molecular Neurodegeneration
- Published
- 2012-04-26
- Volume
- 7
- Issue
- 1
- Pages
- 19-19
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC3407505
- OpenAlex
- W2121634426
- Cited by
- 81
- References
- 5
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 7 · 2020: 12 · 2019: 9 · 2018: 2 · 2017: 6 · 2016: 7 · 2015: 11 · 2014: 9 · 2013: 7 · 2012: 2
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Association (R01AG033007, IIRG-09-129984, ZEN-11-201425)
- Edward N. and Della L. Thome Memorial Foundation
- National Institutes of Health (ZEN-11-201425, IIRG-09-129984)
- National Institute on Aging (R01AG033007)
- National Institute of General Medical Sciences (T32GM007288)
- 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
- gamma-secretase inhibition, familial Danish dementia, synaptic toxicity, memory impairment, Alzheimer's disease, semagacestat, amyloid-beta
- MeSH terms
- Animals, Cataract, Cerebellar Ataxia, Deafness, Dementia, Disease Models, Animal, Enzyme Inhibitors, Memory Disorders, Blotting, Western, Amyloid beta-Protein Precursor, Mice, Amyloid Precursor Protein Secretases, Gene Knock-In Techniques
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