The primary cognitive deficit associated with aging and Alzheimer's disease is impairment of memory processes that require proper hippocampal function. Regulation of Ca2+ is thought to play a role in age-related neurodegeneration and the synaptic plasticity that underlies memory. However, the key elements that link Ca2+ homeostasis with memory or memory impairment remain to be determined. Our work, supported by the preceding award, provides evidence that a decrease in neural transmission through the hippocampus, which is characteristic of age-related memory impairments, results from a shift in susceptibility to induction of synaptic plasticity favoring synaptic depression. The shift in synaptic plasticity is linked to changes in Ca2+ sources with increased contributions from voltage-dependent L-channels and intracellular Ca2+ stores and decreased contributions from NMDA receptors. The Ca2+ dysregulation alters subsequent Ca2+-dependent process, particularly the Ca2+-dependent afterhyperpolarization (AHP), and the activity of the Ca2+-dependent phosphatase, calcineurin, and ultimately gene transcription. In turn, the amplitude of the AHP and level of calcineurin activity regulate synaptic modifiability and are correlated with memory function. Together, these elements provide physiological and biochemical models which link Ca2+ dysregulation to senescent physiology and biochemistry thought to mediate memory. Currently there is a gap in our knowledge concerning the process that leads to Ca2+ dysregulation. Research suggests that oxidative stress can impair Ca2+ homeostasis and synaptic plasticity in a manner similar to that observed during aging. Thus, the current proposal examines oxidative stress as a potential mechanism and target for treatment of Ca2+ dysregulation.
Specific aim 1 will employ conditioning treatments which have been shown to reduce oxidative stress and/or improved memory. We will determine if improved memory is associated with changes in Ca2+- dependent processes as predicted by our model.
Specific aim 2 will apply pharmacological treatments and gene manipulations to reduce oxidative stress to determine if these treatments modify markers of brain aging and improve memory. Specifc aim 3 will addresses the issue of how oxidative stress contributes to calcium dysregulation during aging in the hippocampus by examining the influence of redox state on Ca2+ dependent processes.
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