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Dissertation/Thesis Abstract

Inhibition of amyloid beta-protein fibrillogenesis by myelin basic protein
by Hoos, Michael David, Ph.D., State University of New York at Stony Brook, 2009, 123; 3393652
Abstract (Summary)

Deposition of fibrillar amyloid β-protein (Aβ) in the brain is a prominent pathological feature of Alzheimer disease (AD) and related disorders, including familial forms of cerebral amyloid angiopathy (CAA). Aβ peptides are produced through the successive cleavage of the Aβ precursor protein by β and γ- secretase, producing peptides of between 39 and 43 amino acids in length. The most common of these wild-type peptides are Aβ40 and Aβ42, the first of which being the most abundant. Aβ42 is more fibrillogenic than Aβ40 and has been implicated in early Aβ plaque deposition in AD. 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 biochemical and ultrastructural techniques we identified myelin basic protein (MBP) as a prominent brain parenchymal factor that preferentially binds to the more fibrillogenic CAA mutant Aβ compared with wild-type Aβ40. Further studies demonstrated a similar affinity for the fibrillogenic Aβ42 wild-type peptide. We found that this interaction inhibited the fibril assembly of both CAA mutant Aβ as well as wild-type Aβ42. Structural studies of this interaction have identified a binding region for Aβ in the N-terminus of MBP that alone is sufficient to inhibit Aβ fibrillogenesis through an interaction with the unstructured N-terminus of Aβ peptides. These studies suggest a possible role for MBP in regulating parenchymal fibrillar Aβ deposition in familial CAA and the early formation of amyloid plaques in Alzheimer’s disease. Further study will reveal if peptides derived from MBP show promise as effective inhibitors of amyloid plaques in AD patients.

Indexing (document details)
Advisor: Nostrand, William E. Van
School: State University of New York at Stony Brook
School Location: United States -- New York
Source: DAI-B 71/02, Dissertation Abstracts International
Subjects: Neurosciences, Cellular biology, Biochemistry
Keywords: Alzheimer's disease, Amyloid-beta, Fibrillogenesis, Inhibition, Myelin basic protein
Publication Number: 3393652
ISBN: 978-1-109-61729-0
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