Abstract

Abnormal accumulation and deposition of the amyloid ss-protein (Ass), a prominent pathological feature of patients with Alzheimer's disease (AD) and related disorders, can occur from increased production but in most cases is likely due to decreased clearance mechanisms in the CNS. Clearance mechanisms involve factors that can promote Ass efflux from the CNS, enhance Ass degradation, and/or inhibit Ass assembly and deposition. Although much has been learned about specific molecules that can either influence Ass assembly and deposition or enzymes that can proteolytically degrade Ass our understanding of these processes in brain remains incomplete. Recently, we identified myelin basic protein (MBP) as a novel factor in brain that can bind Ass and potently inhibit its assembly into fibrils. Furthermore, through the course of our recent studies we made the exciting new discovery that MBP, with recently reported serine proteinase activity, can also proteolytically degrade Ass peptides. In light of these novel findings the hypothesis that forms the basis of this proposal is that MBP may contribute to the regulation of Ass levels, amyloid formation, and deposition in brain through its respective proteolytic and fibril-inhibiting activities. The broad objective of this proposal is to better understand these novel activities of MBP that involve its interaction with Ass peptides.
The specific aims of the proposal are as designed to: 1) determine the respective binding regions on MBP and Ass peptides and investigate the consequences of this interaction, 2) characterize the proteolytic activity of MBP and its degradation of Ass, and 3) determine if MBP can modulate Ass levels and amyloid deposition in cell culture models. In the present proposal we plan to implement a multi-faceted approach to investigate how MBP interacts with Ass peptides to regulate their assembly and degradation. We will utilize a combination of biochemical, molecular, ultrastructural, and cell culture approaches to understand these interactions and the consequences of them.

Public Health Relevance

Van Nostrand, William E. Aggregation and deposition of a protein fragment, known as amyloid ss-protein (Ass), in the brain is a key pathological feature of Alzheimer's disease and related disorders. Factors that regulate its degradation and aggregation play an important role in determining if Ass accumulates during disease. The purpose of this proposal is to investigate a newly identified factor that can promote Ass degradation and prevent its aggregation and deposition in brain. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS035781-09S1
Application #
8266866
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Corriveau, Roderick A
Project Start
1997-09-30
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$50,000
Indirect Cost

  Institution

Name
State University New York Stony Brook
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794

  Publications

Kotarba, Annmarie E; Aucoin, Darryl; Hoos, Michael D et al. (2013) Fine mapping of the amyloid ýý-protein binding site on myelin basic protein. Biochemistry 52:2565-73
Ahmed, Mahiuddin; Davis, Judianne; Aucoin, Darryl et al. (2010) Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils. Nat Struct Mol Biol 17:561-7
Liao, Mei-Chen; Hoos, Michael D; Aucoin, Darryl et al. (2010) N-terminal domain of myelin basic protein inhibits amyloid beta-protein fibril assembly. J Biol Chem 285:35590-8
Liao, Mei-Chen; Ahmed, Mahiuddin; Smith, Steven O et al. (2009) Degradation of amyloid beta protein by purified myelin basic protein. J Biol Chem 284:28917-25
Hoos, Michael D; Ahmed, Mahiuddin; Smith, Steven O et al. (2007) Inhibition of familial cerebral amyloid angiopathy mutant amyloid beta-protein fibril assembly by myelin basic protein. J Biol Chem 282:9952-61
Wilhelmus, Micha M M; Otte-Holler, Irene; Davis, Judianne et al. (2005) Apolipoprotein E genotype regulates amyloid-beta cytotoxicity. J Neurosci 25:3621-7
Yamamoto, Naoki; Hirabayashi, Yoshio; Amari, Masakuni et al. (2005) Assembly of hereditary amyloid beta-protein variants in the presence of favorable gangliosides. FEBS Lett 579:2185-90
Jung, Sonia S; Van Nostrand, William E (2003) Humanin rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity. J Neurochem 84:266-72
Jung, Sonia S; Zhang, Weibing; Van Nostrand, William E (2003) Pathogenic A beta induces the expression and activation of matrix metalloproteinase-2 in human cerebrovascular smooth muscle cells. J Neurochem 85:1208-15
Davis, Judianne; Wagner, Matthew R; Zhang, Weibing et al. (2003) Amyloid beta-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells. J Biol Chem 278:19054-61

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