Pathogenic Effects of Cerebral Amyloid Angiopathy Mutations in the Amyloid ?-Protein Precursor
Cerebral amyloid ?-protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. Several mutations have been identified within the A? region of the A? protein precursor (A?PP) gene that appear to enhance the severity of CAA. A new mutation has been identified within the A? region (D23N) of A?PP that is associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double-mutant A?40 peptides rapidly assemble in solution to form fibrils compared to wild-type A?40. Similarly, the E22Q Dutch and D23N Iowa A?40 peptides were found to induce robust pathologic responses in cultured human cerebrovascular smooth muscle (HCSM) cells, including elevated levels of cell-associated A?PP, proteolytic breakdown of actin, and cell death. Double-mutant E22Q/D23N Dutch/Iowa A?40 was more potent than either single-mutant form of A? in causing pathologic responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of A? towards HCSM cells. Moreover, the presence of both CAA substitutions in the same A? peptide further enhances the fibrillogenic and pathogenic properties of A?. We also have generated transgenic mouse models to examine the effects of single and double CAA mutations in A?PP in vivo. Preliminary analysis of transgenic mouse brains indicates that expression of double-mutant E22Q/D23N Dutch/Iowa A?PP leads to robust deposition of A? in a vascular-weighted manner.
mutation cerebral amyloid angiopathy (caa) amyloid ?-protein precursor (a?pp) alzheimer's disease (ad)