Abstract

The long-term goal of this research is to gain an understanding of the cellular and molecular events that lead to neuronal damage and death in Alzheimer's disease (AD). This project tests the hypothesis that beta- amyloid destabilizes cellular calcium homeostasis and thereby renders neurons more vulnerable to environmental insults. A hippocampal cell culture system will be used to examine the cellular and molecular mechanisms whereby beta-amyloid destabilizes neuronal calcium homeostasis, and potentiates excitatory amino acid neurotoxicity. Immunolocalization studies of AD brains are designed to determine whether the neuropathology of AD is consistent with the calcium destabilization hypothesis of beta- amyloid neurotoxicity.
The first aim will test the hypothesis that beta- amyloid affects specific cellular systems for calcium homeostasis (NMDA receptors, calcium channels, Na+/Ca2+ exchanger, calcium binding protein, and calcium ATPase).
The second aim i s to determine whether endogenous beta-amyloid contributes to selective neuronal vulnerability in cell culture.
The third aim i s to establish whether the cytoskeletal manifestations of neuronal degeneration induced by beta-amyloid resemble the neurofibrillary pathology of AD.
The fourth aim i s to determine the relationships of beat-amyloid, NMDA receptors, and calcium-regulating proteins in the histopathology of AD.
These aims will be accomplished using the following technologies: immunocytochemistry to localize beta- amyloid and calcium-regulating proteins in cell cultures and in AD brains; light and confocal laser scanning microscopy in living neurons; electron microscopy; fluorescence ratio imaging of intracellular calcium levels. Each of these techniques will be applied to neurons at different stages in the progression of the neurodegenerative process. Taken together, these studies will: (1) Provide insight into the cellular and molecular mechanisms whereby beta-amyloid destabilizes neuronal calcium homeostasis. (2) Tell us whether the cellular pathology of AD is consistent, at the molecular level, with the calcium-destabilization hypothesis. (3) Generate information that can be used to develop new approaches to preventing and treating the neuronal damage that is responsible for the progression of AD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS030583-01
Application #
3417493
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-06-03
Project End
1996-03-31
Budget Start
1992-06-03
Budget End
1993-03-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Tolar, M; Keller, J N; Chan, S et al. (1999) Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. J Neurosci 19:7100-10
Endres, M; Fink, K; Zhu, J et al. (1999) Neuroprotective effects of gelsolin during murine stroke. J Clin Invest 103:347-54
Blanc, E M; Bruce-Keller, A J; Mattson, M P (1998) Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative stress-induced disruption of Ca2+ homeostasis and cell death. J Neurochem 70:958-70
Blanc, E M; Keller, J N; Fernandez, S et al. (1998) 4-hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes. Glia 22:149-60
Mattson, M P; Furukawa, K (1998) Signaling events regulating the neurodevelopmental triad. Glutamate and secreted forms of beta-amyloid precursor protein as examples. Perspect Dev Neurobiol 5:337-52
Mattson, M P (1998) Free radicals, calcium, and the synaptic plasticity-cell death continuum: emerging roles of the transcription factor NF kappa B. Int Rev Neurobiol 42:103-68
Pedersen, W A; Fu, W; Keller, J N et al. (1998) Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann Neurol 44:819-24
Mattson, M P; Goodman, Y; Luo, H et al. (1997) Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J Neurosci Res 49:681-97
Azbill, R D; Mu, X; Bruce-Keller, A J et al. (1997) Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury. Brain Res 765:283-90
Furukawa, K; Fu, W; Li, Y et al. (1997) The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J Neurosci 17:8178-86

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