Deposition of fibrillar amyloid ␤-protein (A␤) in the brain is a prominent pathological feature of Alzheimer disease and related disorders, including familial forms of cerebral amyloid angiopathy (CAA). Mutant forms of A␤, including Dutch-and Iowa-type A␤, which are responsible for familial CAA, deposit primarily as fibrillar amyloid along the cerebral vasculature and are either absent or present only as diffuse non-fibrillar plaques in the brain parenchyma. Despite the lack of parenchymal

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... l formation in vivo, these CAA mutant A␤ peptides exhibit a markedly increased rate and extent of fibril formation in vitro compared with wild-type A␤. Based on these conflicting observations, we sought to determine whether brain parenchymal factors that selectively interact with and modulate CAA mutant A␤ fibril assembly exist. Using a combination of immunoaffinity chromatography and mass spectrometry, we identified myelin basic protein (MBP) as a prominent brain parenchymal factor that preferentially binds to CAA mutant A␤ compared with wild-type A␤. Surface plasmon resonance measurements confirmed that MBP bound more tightly to Dutch/Iowa CAA double mutant A␤ than to wild-type A␤. Using a combination of biochemical and ultrastructural techniques, we found that MBP inhibited the fibril assembly of CAA mutant A␤. Together, these findings suggest a possible role for MBP in regulating parenchymal fibrillar A␤ deposition in familial CAA. Major mass peaks obtained from the mass spectrometry analysis were submitted to the Mascot search engine. The predicted amino acid sequences are shown. The predicted sequences showed strong alignment with human MBP. Sequence homology (underlined) of the obtained peptide sequences was Ͼ50% for MBP.