Inhibition of familial cerebral amyloid angiopathy mutant amyloid beta-protein fibril assembly by myelin basic protein.
Deposition of fibrillar amyloid beta-protein (Abeta) 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 Abeta, including Dutch- and Iowa-type Abeta, 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 Abeta peptides exhibit a markedly increased rate and extent of fibril formation in vitro compared with wild-type Abeta. Based on these conflicting observations, we sought to determine whether brain parenchymal factors that selectively interact with and modulate CAA mutant Abeta 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 Abeta compared with wild-type Abeta. Surface plasmon resonance measurements confirmed that MBP bound more tightly to Dutch/Iowa CAA double mutant Abeta than to wild-type Abeta. Using a combination of biochemical and ultrastructural techniques, we found that MBP inhibited the fibril assembly of CAA mutant Abeta. Together, these findings suggest a possible role for MBP in regulating parenchymal fibrillar Abeta deposition in familial CAA.
Hoos
Michael D
MD
Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153.
Ahmed
Mahiuddin
M
Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794-8153.
Smith
Steven O
SO
Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794-8153.
Van Nostrand
William E
WE
Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153. Electronic address: William.VanNostrand@stonybrook.edu.
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000502:physiology*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D004676:Myelin Basic Protein