Abstract
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.
Highlights
(APP), a large type I integral membrane protein, through sequential proteolysis by - and ␥-secretase activities [3,4,5,6]
We identified myelin basic protein (MBP) as an endogenous brain protein that preferentially binds to familial cerebral amyloid angiopathy (CAA) mutant forms of A
We show that MBP effectively inhibits the fibrillar assembly of CAA mutant A by biochemical methods as well as by transmission electron microscopy (TEM) and atomic force microscopy (AFM)
Summary
We found that including each of these mutations together in the same A peptide (Dutch/Iowa CAA double mutant A40 peptide (A40DI)) further enhances the fibrillogenic and pathogenic properties in vitro [34]. Other reported A chaperones that may influence A fibril assembly include ␣1-antichymotrypsin [47, 48], transthyretin [49, 50], proteoglycans [51, 52], and gangliosides [53, 54] In these reports, the study of the interaction of chaperones was restricted to wild-type A peptides. The study of the interaction of chaperones was restricted to wild-type A peptides The involvement of these A chaperones in promoting or inhibiting CAA mutant A fibril formation remains largely unknown. With this in mind, one approach we have taken is to identify molecules that preferentially bind to CAA mutant forms of A and that may modulate their fibrillar assembly. We postulate that MBP may be involved, at least in part, in regulating the compartment-specific fibrillar deposition of CAA mutant A within the brain
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