The hypothesis to be tested is that nerve cells which contain Calbindin- D28K (CaBP) are relatively resistant to degeneration and death in Alzheimer's disease (AD). Decreased CaBP levels may be a primary determinant of neuronal vulnerability in specific brain areas targeted by AD. Since intracellular calcium (Ca2+) plays a major role in many aspects of neuronal development, function, aging, and degeneration, understanding neuronal Ca2+ homeostasis is of paramount importance relative to normal function and potential pathologies. Ca2+ regulation is achieved through the integration of multiple mechanisms which control different aspects of Ca2+ influx, efflux, and sequestration. One component of the Ca2+ sequestration system, the calcium binding protein CaBP, has received increasing attention due to recent evidence suggesting that differences in CABP content may account for selective neuronal vulnerability seen in aging/neurodegenerative diseases. Recent studies have demonstrated substantial alterations in Ca2+ homeostasis in AD. One of the principle neuropathological features of AD, the neurofibrillary tangle (NFT), has been shown to develop through Ca2+-mediated mechanisms. All of this evidence has been derived from animal or in-vitro studies but, to date, not in the AD brain. This proposal is designed to provide evidence for the neuroprotective effect of CaBP relative to the nucleus basalis of Meynert (NB) in the human brain. If CaBP is protecting these neurons from neurodegeneration in AD, then: 1) CaBP levels within individual neurons may be altered during the course of the disease; and 2) CaBP may inhibit NFT formation during the early stage of AD when there is minimal cell loss. We will measure cell number and size, CaBP levels, and presence of NFT's within the NB neurons in short and moderate duration cases of AD as well as age-matched non-demented controls. A newly developed radioimmunocytochemical procedure for quantification of intracellular CaBP content (pg/cell), sensitive NFT immunocytochemistry, and computer imaging techniques will be utilized in the proposed studies.
The specific aims of the proposal are: 1) to quantitate CaBP in individual NB neurons; 2) to localize NFT's in these neurons; and 3) to determine whether neurons with higher amounts of CaBP contain fewer NFT's. The quantitative data obtained will help clarify whether CaBP serves a neuroprotective role in AD. Demonstration of a neuroprotective function may elucidate the selective vulnerability of neurons devoid of CaBP and related intracellular Ca2+ binding proteins. This will enable future design of strategies aimed at prevention/treatment of neurodegenerative disorders such as AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Center Core Grants (P30)
Project #
3P30AG012300-06S2
Application #
6218758
Study Section
Project Start
1999-08-15
Project End
2000-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
Schaffert, Jeff; LoBue, Christian; White, Charles L et al. (2018) Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease. Neuropsychology 32:410-416
Rosenberg, Roger N; Fu, Min; Lambracht-Washington, Doris (2018) Intradermal active full-length DNA A?42 immunization via electroporation leads to high anti-A? antibody levels in wild-type mice. J Neuroimmunol 322:15-25
Davis, Jeremy J (2018) Performance validity in older adults: Observed versus predicted false positive rates in relation to number of tests administered. J Clin Exp Neuropsychol 40:1013-1021
Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27
Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307
Pottier, Cyril; Zhou, Xiaolai; Perkerson 3rd, Ralph B et al. (2018) Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol 17:548-558
Crum, Jana; Wilson, Jeffrey; Sabbagh, Marwan (2018) Does taking statins affect the pathological burden in autopsy-confirmed Alzheimer's dementia? Alzheimers Res Ther 10:104
Burke, Shanna L; Cadet, Tamara; Maddux, Marlaina (2018) Chronic Health Illnesses as Predictors of Mild Cognitive Impairment Among African American Older Adults. J Natl Med Assoc 110:314-325
Weintraub, Sandra; Besser, Lilah; Dodge, Hiroko H et al. (2018) Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS). Alzheimer Dis Assoc Disord 32:10-17
Kamara, Dennis M; Gangishetti, Umesh; Gearing, Marla et al. (2018) Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. J Alzheimers Dis 62:1815-1826

Showing the most recent 10 out of 385 publications