The Familial Dementia BRI2 Gene Binds the Alzheimer Gene Amyloid-β Precursor Protein and Inhibits Amyloid-β Production
Open accessAbstract
Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-beta (A(beta)) peptides, which are derive from processing of the beta-amyloid precursor protein (APP), better named amyloid-beta precursor protein (A(beta)PP), by secretases. The A(beta)PP intracellular domain (AID), which is released together with A(beta), has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating A(beta)PP processing are poorly understood. As cleavage of other gamma-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind A(beta)PP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with A(beta)PP. Interestingly, 17 amino acids corresponding to the NH2-terminal portion of A(beta) are necessary for this interaction. Moreover, BRI2 expression regulates A(beta)PP processing resulting in reduced A(beta) and AID levels. Altogether, these findings characterize the BRI2-A(beta)PP interaction as a regulatory mechanism of A(beta)PP processing that inhibits A(beta) production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the…
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Previous studies demonstrated a potential interaction between BRI2 and APP.
“Previous studies had demonstrated a potential interaction between BRI2 and APP and noted that BRI2 overexpression increased APP C-terminal fragment  (CTF) and reduced A secretion in cultured cells (Fotinopoulou et al., 2005;Matsuda et al., 2005).”
From BRI2 (ITM2b) Inhibits A Deposition In Vivo (2008) · cites this paper as Matsuda et al., 2005
BRI2 overexpression increased APP C-terminal fragment β (CTFβ) and reduced Aβ secretion in cultured cells.
“Previous studies had demonstrated a potential interaction between BRI2 and APP and noted that BRI2 overexpression increased APP C-terminal fragment  (CTF) and reduced A secretion in cultured cells (Fotinopoulou et al., 2005;Matsuda et al., 2005).”
From BRI2 (ITM2b) Inhibits A Deposition In Vivo (2008) · cites this paper as Matsuda et al., 2005
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References 30 · Cited by 141
- Authors
- Matsuda, S., Giliberto, L., Matsuda, Y., Davies, P., McGowan, E., Pickford, F., Ghiso, J., Frangione, B., & D'Adamio, L.
- Affiliations
- Albert Einstein College of Medicine (US)
- Mayo Clinic (US)
- New York University (US)
- Corresponding author
- D'Adamio, Luciano
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 280
- Issue
- 32
- Pages
- 28912-28916
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1965577101
- Cited by
- 141
- References
- 30
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 11 · 2019: 4 · 2018: 7 · 2017: 4 · 2016: 10 · 2015: 7 · 2014: 6 · 2013: 6 · 2012: 8
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag005891-11)
- National Institute on Aging (R01 AG05891, R01AG022595, R01AG022024, R01AG008721, R01AG21588, R01AG22024, R01AG021588, R01 AG08721)
- National Institute of Neurological Disorders and Stroke (R01NS38777, R01NS038777)
- 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
- BRI2, amyloid precursor protein, amyloid-beta production, Alzheimer's disease, familial British dementia, familial Danish dementia, APP intracellular domain, protein-protein interaction, type II membrane protein, pathogenic variants
- MeSH terms
- Alzheimer Disease, Amyloid, Brain, Cell Line, Cell Membrane, Cytoplasm, Dementia, Enzyme-Linked Immunosorbent Assay, HeLa Cells, Humans, Ligands, Luciferases, Membrane Glycoproteins, Membrane Proteins, Mutation, Peptides, Plasmids, Protein Binding, Transcription, Genetic, Transfection, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Apoptosis, Protein Structure, Tertiary, Two-Hybrid System Techniques, Adaptor Proteins, Signal Transducing
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