The long-term objectives of this research are to understand the mechanisms which underlie the cytoskeletal alterations associated with Alzheimer's disease neuropathology. It is increasingly clear that factors other than tau hyperphosphorylation are involved in the formation of neurofibrillary tangles. This application will examine the hypothesis that much of the cytoskeletal disruption evident in neurofibrillary tangles can occur independently of tau hyperphosphorylation. It is proposed that several types of neuronal insult (i.e., metabolic impairment, oxidative stress, sustained depolarization) result in the loss of tau from axons, accumulation in the somatodendritic compartment, and sparing of tau relative to other cytoskeletal proteins (i.e., MAP2, tubulin, neurofilaments). The hyperphosphorylation of tau could be a consequence of its redistribution and occur during recovery from neuronal insult. Experiments proposed in this application will employ primary cultures of rat hippocampal neurons. Results obtained following experimental manipulation of the cultures will expand upon evidence already obtained in vivo. The specific questions which this proposal aims to answer include: 1) Do neuronal insults which enhance perikaryal tau immunostaining also cause a redistribution or loss of other cytoskeletal proteins? Do they alter tau phosphorylation? 2) Does the spatial and temporal pattern of cytoskeletal disruption correlate with alterations in intracellular calcium levels? 3) Are oxidative stress and calpain activation involved in the redistribution and loss of cytoskeletal proteins following neuronal insult? Could calpain substrate specificity account for the sparing of tau relative to other cytoskeletal proteins? 4) Do insults which result in the perikaryal accumulation of tau also impair the ability of tau to bind to microtubules and/or facilitate the aggregation of tau into filamentous structures? 5) Could the hyperphosphorylation of tau occur during recovery from neuronal insult? 6) Does the cytoskeletal disruption observed following neuronal insult in vitro resemble alterations in Alzheimer's disease? Experimental methodologies include primary neuronal culture, immunocytochemistry, immunoblots, confocal and transmission electron microscopy, calcium imaging, and assays for MAP kinase and calpain activity, free radical production, tau phosphorylation, and microtubule binding.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
3P50AG005144-16S2
Application #
6218668
Study Section
Project Start
1999-08-15
Project End
2000-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
16
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Broster, Lucas S; Li, Juan; Wagner, Benjamin et al. (2018) Spared behavioral repetition effects in Alzheimer's disease linked to an altered neural mechanism at posterior cortex. J Clin Exp Neuropsychol 40:761-776
Petyuk, Vladislav A; Chang, Rui; Ramirez-Restrepo, Manuel et al. (2018) The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target. Brain 141:2721-2739
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Reed, Rebecca G; Greenberg, Richard N; Segerstrom, Suzanne C (2017) Cytomegalovirus serostatus, inflammation, and antibody response to influenza vaccination in older adults: The moderating effect of beta blockade. Brain Behav Immun 61:14-20
Li, Juan; Broster, Lucas S; Jicha, Gregory A et al. (2017) A cognitive electrophysiological signature differentiates amnestic mild cognitive impairment from normal aging. Alzheimers Res Ther 9:3
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-121
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-200.e20
Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-150
Wei, Shaoceng; Kryscio, Richard J (2016) Semi-Markov models for interval censored transient cognitive states with back transitions and a competing risk. Stat Methods Med Res 25:2909-2924

Showing the most recent 10 out of 236 publications