The long-term goals of this proposed research are to understand the mechanisms governing degenerative processes in aging, Alzheimer's disease, and other age-related pathologies. Specifically, this project focuses on an enzyme (calpain) whose substrates include brain spectrin and the neurofilament and microtubule-associated proteins. Calpain is a calcium-activated neutral protease that has been implicated in both experimentally- induced and disease-related degeneration. It is present in neurons that are particularly susceptible to age-related pathology, and its activity in brain is linearly and negatively correlated with the maximal life span of eight orders of mammals.
The specific aims of this proposed research are (1) to compare the cellular and subcellular distribution of calpain and three of its substrates, brain spectrin, the 200 kD neurofilament protein, and microtubule-associated protein 2 in young adult, mid-life, and elderly rats, (2) to localize calpain and the abovementioned substrates in human autopsy material from patients with Alzheimer's disease, amyotrophic lateral sclerosis, multiple infraction dementia and normal aging at the light and electron microscopic levels, (3) to determine whether calpain is located in or near neurofibrillary tangles or neuritic plaques, (4) to evaluate whether there is a selective loss of calpain containing cells in Alzheimer's disease, and (5) to test whether calpain's activity, or the concentration of the enzyme or its substrates, is altered in age or age-related disease. Thus, this proposed research seeks to determine the role of calpain in the cellular degeneration that accompanies age and pathology. To accomplish this end, light and electron microscopic examination of immunostained tissue, biochemical assay of enzyme activity, and immunoblots will be used. These studies should significantly add to our understanding of the mechanisms involved in the cytoskeletal disarray seen with age and age-related pathologies, as well as to delineate differences and similarities between these different pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AG007127-04
Application #
3453111
Study Section
Neurology A Study Section (NEUA)
Project Start
1987-09-01
Project End
1992-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Perlmutter, L S; Myers, M A; Barron, E (1994) Vascular basement membrane components and the lesions of Alzheimer's disease: light and electron microscopic analyses. Microsc Res Tech 28:204-15
Perlmutter, L S (1994) Microvascular pathology and vascular basement membrane components in Alzheimer's disease. Mol Neurobiol 9:33-40
Scott, S A; Johnson, S A; Zarow, C et al. (1993) Inability to detect beta-amyloid protein precursor mRNA in Alzheimer plaque-associated microglia. Exp Neurol 121:113-8
Perlmutter, L S; Scott, S A; Barron, E et al. (1992) MHC class II-positive microglia in human brain: association with Alzheimer lesions. J Neurosci Res 33:549-58
Perlmutter, L S; Barron, E; Saperia, D et al. (1991) Association between vascular basement membrane components and the lesions of Alzheimer's disease. J Neurosci Res 30:673-81
Perlmutter, L S; Barron, E; Chui, H C (1990) Morphologic association between microglia and senile plaque amyloid in Alzheimer's disease. Neurosci Lett 119:32-6
Perlmutter, L S; Chui, H C; Saperia, D et al. (1990) Microangiopathy and the colocalization of heparan sulfate proteoglycan with amyloid in senile plaques of Alzheimer's disease. Brain Res 508:13-9
Perlmutter, L S; Gall, C; Baudry, M et al. (1990) Distribution of calcium-activated protease calpain in the rat brain. J Comp Neurol 296:269-76
Perlmutter, L S; Chui, H C (1990) Microangiopathy, the vascular basement membrane and Alzheimer's disease: a review. Brain Res Bull 24:677-86