β‐ but not γ‐secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia
Open accessAbstract
A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ.
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Accumulation of sAPPβ and/or β-CTF may affect long-term potentiation and memory acquisition in mouse models.
“For example, the accumulation of amino-terminal-soluble APPβ (sAPPβ) and/or β-carboxyl-terminal fragments (β-CTF) may affect long-term potentiation (LTP) [5] and memory acquisition in mouse models [6].”
From Normal cognition in transgenic BRI2-Aβ mice (2013) · cites this paper as [6]
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Self-citation
- Authors
- Tamayev, R., Matsuda, S., Arancio, O., & D'Adamio, L.
- Affiliations
- Albert Einstein College of Medicine (US)
- Columbia University (US)
- Corresponding author
- D'Adamio, Luciano
- Venue
- EMBO Molecular Medicine
- Published
- 2012-01-23
- Volume
- 4
- Issue
- 3
- Pages
- 171-179
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3376850
- OpenAlex
- W2148957789
- Cited by
- 142
- References
- 8
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 9 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 14 · 2019: 13 · 2018: 8 · 2017: 13 · 2016: 12 · 2015: 13 · 2014: 12 · 2013: 9 · 2012: 9
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (IIRG‐09‐129984)
- National Institutes of Health (R01AG033007)
- 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
- amyloid precursor protein, beta-secretase, gamma-secretase, familial Danish dementia, Alzheimer's disease, amyloid-beta, synaptic deficits, memory impairment, APP cleavage, anti-amyloid therapy, therapeutic target
- MeSH terms
- Animals, Cataract, Cerebellar Ataxia, Deafness, Dementia, Disease Models, Animal, Enzyme Inhibitors, Humans, Membrane Proteins, Memory, Neuronal Plasticity, Synapses, Amyloid beta-Peptides, Mice, Knockout, Adaptor Proteins, Signal Transducing, Mice, Amyloid Precursor Protein Secretases, Proteolysis
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