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 #
5P30AG012300-05
Application #
6267630
Study Section
Project Start
1998-04-15
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2018) Decreasing hazards of Alzheimer's disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E. Int J Geriatr Psychiatry 33:200-211
Qian, Winnie; Fischer, Corinne E; Schweizer, Tom A et al. (2018) Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease. Curr Alzheimer Res 15:187-194
Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827
Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600
Hanfelt, John J; Peng, Limin; Goldstein, Felicia C et al. (2018) Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center. Neurobiol Dis 117:62-71
Zhou, Zilu; Wang, Weixin; Wang, Li-San et al. (2018) Integrative DNA copy number detection and genotyping from sequencing and array-based platforms. Bioinformatics 34:2349-2355
Stallings, Nancy R; O'Neal, Melissa A; Hu, Jie et al. (2018) Pin1 mediates A?42-induced dendritic spine loss. Sci Signal 11:
Burke, Shanna L; Hu, Tianyan; Fava, Nicole M et al. (2018) Sex differences in the development of mild cognitive impairment and probable Alzheimer's disease as predicted by hippocampal volume or white matter hyperintensities. J Women Aging :1-25

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