BRI2-Related Mechanisms in Familial Dementias

The integral membrane protein BRI2, encoded by the ITM2B gene, is central to the pathogenesis of rare inherited dementias such as familial British and Danish dementia. Pathogenic mutations in ITM2B alter proteolytic processing of BRI2, yielding extended C-terminal amyloid peptides (known as ABri and ADan) that aggregate extracellularly, seed tau pathology and drive neurodegeneration. Beyond amyloid formation, loss of native BRI2 function perturbs the normal cleavage of amyloid precursor protein (APP), favouring the production of toxic APP fragments. Recent studies have revealed that BRI2 is highly enriched in microglia, where it regulates both innate immune responses and interplays with key receptors such as TREM2. Additional modulators—including proteases like furin and chaperone interactions mediated by the BRICHOS domain—further influence BRI2 trafficking, stability and amyloidogenic potential. Together, these findings position BRI2 at the intersection of amyloid biology, glial activation and synaptic dysfunction, underscoring its global significance as both a mechanistic linchpin and a candidate therapeutic target in familial and possibly sporadic dementias.

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Technical terms

BRI2 (ITM2B): A type II transmembrane protein whose mutations cause familial British and Danish dementias by producing amyloidogenic peptides.

ABri peptide: An insoluble C-terminal fragment of mutant BRI2 generated in familial British dementia that forms extracellular amyloid plaques.

Microglia: Resident immune cells of the central nervous system that contribute to amyloid production and clearance in neurodegenerative diseases.

TREM2: A microglial surface receptor that regulates phagocytosis and inflammatory signalling; its proteolytic processing is modulated by BRI2.

BRICHOS domain: A conserved chaperone motif within BRI2 that influences protein folding and aggregation of amyloidogenic fragments.

Furin: A proprotein convertase that cleaves BRI2 at a specific site, influencing the release of amyloid peptides and protein trafficking.

References

1. Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia. Acta Neuropathologica (2024).
2. Functional BRI2-TREM2 interactions in microglia: implications for Alzheimer’s and related dementias. EMBO Reports (2024).
3. Myelin Basic Protein Attenuates Furin-Mediated Bri2 Cleavage and Postpones Its Membrane Trafficking. International Journal of Molecular Sciences (2024).
4. BRI2 Interacts with Amyloid Precursor Protein (APP) and Regulates Amyloid β (Aβ) Production*. Journal of Biological Chemistry (2005).