Inhibition of familial cerebral amyloid angiopathy mutant amyloid β-protein fibril assembly by myelin basic protein

Deposition of fibrillar amyloid beta-protein (A beta) 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 beta, including Dutch- and Iowa-type A beta, 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 fibril formation in vivo, these CAA mutant A beta peptides exhibit a markedly increased rate and extent of fibril formation in vitro compared with wild-type A beta. Based on these conflicting observations, we sought to determine whether brain parenchymal factors that selectively interact with and modulate CAA mutant A beta 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 beta compared with wild-type A beta. Surface plasmon resonance measurements confirmed that MBP bound more tightly to Dutch/Iowa CAA double mutant A beta than to wild-type A beta. Using a combination of biochemical and ultrastructural techniques, we found that MBP inhibited the fibril assembly of CAA mutant A beta. Together, these findings suggest a possible role for MBP in regulating parenchymal fibrillar A beta deposition in familial CAA.