Cumulative exposure to glucocorticoids (GCs) is a major determinant of the rate of hippocampal neuron loss during aging; moreover, GCs can impair the capacity of the hippocampus to survive varied neurological insults. Our ongoing work focuses on two themes: a) GCs exacerbate the toxicity of these hippocampal insults by exacerbating the """"""""glutamate/NMDA/calcium"""""""" cascade of damage. b) These GC actions derive from the catabolic effects of GCs upon metabolism in these neurons. We are obtaining support for these ideas, and the present grant explores their implications. 1) If, as we find, GCs exacerbate this cascade, then GCS should also exacerbate calcium-dependent degenerative events in the hippocampus. Our pilot data strongly support this and we will explore this further, looking at GC modulation of calcium-dependent proteolysis of spectrin, and accumulation of tau and ubiquitin antigenicity. We will determine the physiological relevance of such GC modulation and its role in the senescent hippocampus. Work will be both in vivo and in primary hippocampal cultures. 2) A growing literature suggests that fragments of the amyloid precursor protein can be toxic to hippocampal neurons. Working both in vivo and in vitro, we will attempt to replicate reports regarding such toxicity, and then determine whether it is modulated by GCs. If so, we will explore the physiological relevance and role in hippocampal aging of such GC actions. 3) GCs inhibit glucose uptake in the hippocampus and depress concentrations of energy substrates. We will use a novel microphysiometer to detennine whether GCs depress metabolism in hippocampal neurons or accelerate the metabolic decline observed during neurological insults. We will also examine whether amyloid fragments depress metabolism as well.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Modified Research Career Development Award (K04)
Project #
5K04AG000563-04
Application #
2048326
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-08-10
Project End
1997-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Stein-Behrens, B A; Lin, W J; Sapolsky, R M (1994) Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63:596-602
Sapolsky, R M (1993) Potential behavioral modification of glucocorticoid damage to the hippocampus. Behav Brain Res 57:175-82