ITM2B encodes an integral membrane protein with critical roles in neuronal function and amyloid homeostasis. Functionally, ITM2B/BRI2 facilitates glutamatergic synaptic transmission through dual presynaptic and postsynaptic mechanisms 1, regulating both spontaneous glutamate release and AMPAR-mediated responses 2. The protein also binds amyloid-beta and prevents its aggregation into toxic oligomers [UniProt]. Pathogenic mechanisms involve two processes: loss of BRI2 function and accumulation of amyloidogenic peptides. Mutations near the stop codon cause C-terminal extension, generating disease-specific peptides (ABri in familial British dementia, ADan in familial Danish dementia) that form extracellular amyloid deposits 3. Notably, microglia are major contributors to ABri peptide production, suggesting microglial dysfunction drives pathogenesis 4. Reduced BRI2 protein stability from pathogenic mutations diminishes functional protein at synapses, impairing glutamatergic transmission 2. Clinically, ITM2B mutations cause early-onset cerebral amyloid angiopathy, familial British dementia, familial Danish dementia, and ITM2B-related retinal dystrophy 56. Emerging evidence shows ITM2B truncation also promotes renal cell carcinoma progression through migrasome formation 7. Understanding ITM2B pathophysiology may inform therapeutic strategies targeting excitatory neurotransmitter dysfunction in neurodegenerative disease.