The effects of A beta PP mutations and APOE polymorphisms on cerebral amyloid angiopathy

Analysis of causative mutations and genetic risk factors aid in the underst anding of important processes of cerebral amyloid angiopathy, (CAA) in huma ns. We identified a initiation at a novel site of the beta -amyloid precurs or protein (A beta PP) gene associated with familial CAA; this initiation c auses an aspartate to asparagine substitution at position 23 of the A beta peptide. Neuropathological analysis of a 68-year-old man with this mutation showed dramatic A beta deposition in blood vessels, diffuse parenchymal A beta deposits, dystrophic neurites and neurofibrillary, tangles. The A beta deposition showed complete co-localization of A beta 40 and A beta 42, com pared to the predominant A beta 42 deposition seen in AD. We hypothesize th at the loss of an acidic residue at position 23 of A beta might be importan t in the process of A beta aggregation on smooth muscle cells on the cerebr ovasculature. We also analyzed how the apolipoprotein E (APOE) gene might influence aggre gation of A beta by examining the physical association of apoE domains with A beta via immunohistochemistry We found that the lipid-binding domain of apoE was more strongly, associated with A beta than the receptor binding do main, and that 40% of all A beta deposits had no apoE bound to them, We sug gest that the initial deposition of A beta occurs in the absence of apoE, a nd that the process of A beta deposit growth or stabilization is apoE-depen dent.