N-terminal Domain of Myelin Basic Protein Inhibits Amyloid β-Protein Fibril Assembly

Abstract

In the present study, we demonstrate that human MBP purified from either brain or a bacterial recombinant expression system comparably bound to A␤ and inhibited A␤ fibril assembly indicating that post-translational modifications are not required for this activity. We also show that purified mouse brain MBP and recombinantly expressed mouse MBP similarly inhibited A␤ fibril formation. Through a combination of biochemical and ultrastructural techniques, we demonstrate that the binding site for A␤ is located in the N-terminal 64 amino acids of MBP and that a stable peptide (MBP1) comprising these residues was sufficient to inhibit A␤ fibrillogenesis. Under conditions comparable with those used for A␤, the fibrillar assembly of amylin, another amyloidogenic peptide, was not inhibited by MBP1, although MBP1 still bound to it. This observation suggests that the potent inhibitory effect of MBP on fibril formation is not general to amyloidogenic peptides. Finally, MBP1 could prevent the cytotoxic effects of A␤ in primary cortical neurons. Our findings suggest that inhibition of A␤ fibril assembly by MBP, mediated through its N-terminal domain, could play a role in influencing amyloid formation in Alzheimer disease brain and corresponding mouse models. The histopathology of Alzheimer disease (AD)2 is characterized by the prominent presence of plaques of amyloid ␤-protein (A␤) in the brain parenchyma (1). Dystrophic neurons and neuronal loss are often associated with A␤ accumulation leading to the clinical manifestation of cognitive decline and memory loss. A␤ is derived from the amyloid ␤-protein precursor (A␤PP) through sequential proteolysis by ␤-and ␥-secretases yielding peptides of between 39 and 43 residues (2-5). These peptides exhibit a high propensity to self-assemble into ␤-sheet-containing oligomers and fibrils of which the oligomeric forms are widely believed to be the most toxic species of the peptide, responsible for the majority of neuronal loss (6). A condition known as cerebral amyloid angiopathy (CAA) is prevalently found in AD and is characterized by fibrillar deposition of A␤ along arteries and arterioles of the cerebral cortex, leptomeninges, and cerebral microvasculature (6 -8). Apart from the more typical CAA, which commonly occurs in AD, familial forms of CAA exist that are the result of specific point mutations within the A␤ sequence of the A␤PP gene (9 -15). Two well studied examples of familial CAA are Dutch type, resulting from an E22Q substitution in A␤ (9, 10), and Iowa type, resulting from a D23N substitution in A␤ (15).Elucidating the molecules and processes in brain that regulate A␤ assembly and accumulation as parenchymal plaques and cerebral vascular deposits is important for understanding the pathogenesis of AD and related disorders as well as for providing opportunities for development of potential therapeutic interventions. Previously, we found that myelin basic protein (MBP) strongly bound to a highly fibrillogenic A␤40 peptide that contains both the Dutch and Iowa mutations (A␤40DI)...

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…1). Some endogenous inhibitors of Aβ aggregation, such as the secreted ectodomain of tumour necrosis factor receptor superfamily member 16 (also known as low affinity neurotrophin receptor p75NTR) 19 and the N-terminal domain of myelin basic protein 20 , prevent Aβ deposition in the brain and facilitate its efflux into the circulation.…”

Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer's disease mouse model

“…MBP can bind Aβ peptides and inhibit the assembly of fibrillar Aβ [52]; it also can prevent Aβ-mediated cytotoxicity [53], and degrade fibrillar Aβ in vitro and vivo [54], indicating that MBP possesses Aβ-degrading activity.…”

The N-terminal region of myelin basic protein reduces fibrillar amyloid-β deposition in Tg-5xFAD mice

“…Expression of MBP isoforms is developmentally regulated, with the 18.5 kDa species being the most prevalent isoform in mature human brain (de Ferra et al, 1985; Harauz et al, 2004). While endogenous MBP proteins possess numerous post-translational modifications to give rise to various charged isomers, the use of recombinant MBP suggested the inhibition of Aβ fibril assembly was independent of these modifications (Liao et al, 2010). Further, using deletion mutants it was shown that the N-terminal 1–64 amino acids of MBP (MBP1), harbored the Aβ interacting site and is capable of inhibiting Aβ fibril assembly (Liao et al, 2010).…”

“…While endogenous MBP proteins possess numerous post-translational modifications to give rise to various charged isomers, the use of recombinant MBP suggested the inhibition of Aβ fibril assembly was independent of these modifications (Liao et al, 2010). Further, using deletion mutants it was shown that the N-terminal 1–64 amino acids of MBP (MBP1), harbored the Aβ interacting site and is capable of inhibiting Aβ fibril assembly (Liao et al, 2010). In addition, synthetic MBP1 protected cultured primary rat neurons from the cytotoxic effects of Aβ (Liao et al, 2010).…”