Inhibition of Familial Cerebral Amyloid Angiopathy Mutant Amyloid β-Protein Fibril Assembly by Myelin Basic Protein

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