A Shift in Microglial -Amyloid Binding in Alzheimer's Disease Is Associated with Cerebral Amyloid Angiopathy

Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are two common pathologies associated with -amyloid (A) accumulation and inflammation in the brain; neither is well understood. The objective of this study was to evaluate human post-mortem brains from AD subjects with purely parenchymal pathology, and those with concomitant CAA (and age-matched controls) for differential expression of microglia-associated A ligands thought to mediate A clearance and the association of these receptors with complement activation. Homogenates of brain parenchyma and enriched microvessel fractions from occipital cortex were probed for levels of C3b, membrane attack complex (MAC), CD11b and -2-macroglobulin and immunoprecipitation was used to immunoprecipitate (IP) CD11b complexed with C3b and A. Both C3b and MAC were significantly increased in CAA compared to AD-only and controls and IP showed significantly increased CD11b/C3b complexes with A in AD/CAA subjects. Confocal microscopy was used to visualize these interactions. MAC was remarkably associated with CAA-affected blood vessels compared to AD-only and control vessels. These findings are consistent with an A clearance mechanism via microglial CD11b that delivers A and C3b to blood vessels in AD/CAA, which leads to A deposition and propagation of complement to the cytolytic MAC, possibly leading to vascular fragility.