MOLECULAR BASIS OF NEUROLOGICAL CHANGES DURING AGING

Project: Research project

Project Details

Description

Several factors contribute to the degeneration and ultimately loss of neurons during aging and especially during Alzheimer's Disease (AD). One potentially critical factor is an increase in neuronal Ca2+ influx through L-type Ca2+ channels. The activity of L-type channels increases with age in rats, and an inhibitor of these channels impressively improves the learning capabilities of aged rabbits when given over several weeks. These findings suggest that L-type channels may be involved in aging-related neurological changes and the etiology of AD. Our objectives are to determine molecular changes of L-type channels that may contribute to the upregulation of L-type channel activity during aging. Based on our preliminary data, we hypothesize that: (A) an increase in protein kinase A (PKA)-mediated phosphorylation of L-type channels is responsible for their upregulation during aging; (B) beta-adrenergic receptors can control the elevation in phosphorylation of L-type channels by PKA. We will test these hypotheses by determining the phosphorylation status of L-type channels in brain samples from adult rats (some treated with beta-adrenergic agonists) and aging rats as a model for senile symptoms. Brain samples from adult and aging rats will be solubilized and L-type channels immunoprecipitated for further biochemical analysis of parameters that might change during aging, e.g., phosphorylation by PKA and other kinases. To test whether the number of L-type channels present in neurons is changed during aging, relative amounts of L-type channel proteins will be determined by immunoblotting and compared to the level of various pre- and postsynaptic marker proteins. PKA is associated with L-type channels. We will measure the relative amounts of PKA subunits and PKA anchoring proteins in the L-type channel immunocomplexes to test potential changes during aging that could explain the increase in PKA-mediated phosphorylation. Finally, we will investigate whether injection of the beta-adrenergic agonist isoproterenol upregulates PKA-mediated phosphorylation of L-type channels in adult rats.
StatusFinished
Effective start/end date12/1/998/31/16

Funding

  • National Institutes of Health: $381,452.00
  • National Institutes of Health: $357,460.00
  • National Institutes of Health: $301,350.00
  • National Institutes of Health: $307,500.00
  • National Institutes of Health: $347,049.00
  • National Institutes of Health: $368,181.00
  • National Institutes of Health: $301,350.00
  • National Institutes of Health: $304,386.00
  • National Institutes of Health: $379,225.00
  • National Institutes of Health: $330,061.00
  • National Institutes of Health: $293,452.00

ASJC

  • Medicine(all)

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