The topic of this proposal is the origin of paired helical filaments (PHF), a major pathological feature of Alzheimer's disease (AD). Although several lines of evidence point towards neuronal cytoskeletal proteins as possible constituents of PHF, their chemical composition remains uncertain. The task we now confront is to unravel the mechanisms that lead to the development of PHF and to ascertain their molecular origin. Our general hypothesis is that PHF are derived from neurofilament or tau proteins that are modified during the course of a disease, such as AD, or by aging. To explore this hypothesis, we propose the following strategies: . To study the in vitro assembly of normal neurofilament and tau proteins; . To submit these cytoskeletal proteins to chemical modifications in vitro and to observe the structural changes that ensue (i.e., formation of insoluble polymers or PHF). The effects of multivalent cations and partial proteolysis have been chosen as conditions that are relevant to posttranslational modifications that may lead to pathological changes of the cytoskeleton in vivo, such as occurs in AD; and . To compare the in vitro assembly of neurofilament and tau proteins isolated from the brains of individuals with AD to those of controls.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025369-03
Application #
3410636
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-02-01
Project End
1992-01-31
Budget Start
1990-02-01
Budget End
1991-01-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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