The aged Long-Evans hippocampus exhibits altered gene expression and reduced receptor-effector function without major loss of synaptic processes. The hippocampus of the aged learning-impaired subject contains significant levels of oxidized protein and DNA; Mn-SOD mRNA, and heme oxygenase-1 protein are induced; mitochondrial DNA integrity is comprised; and NF-kappaB and Akt are activated. These findings suggest that aged hippocampal neurons initiate survival mechanisms in response to oxidative stress. The cholinergic neuronal population that innervates hippocampus declines 23% in number and gene expression patterns suggest that these neurons experience reduced neurotrophin influence. We propose to evaluate the functional status of hippocampal mitochondria and determine whether they are a source of oxidative stress. We will determine whether synaptic plasticity systems are comprised and evaluate the extent to which cellular survival reactions occur in the basal forebrain and hippocampus. Additionally, we will combine laser-assisted microdissection with gene microarray analysis, in collaboration with the Lund project, to evaluate phenotypic, homeostatic, survival, and plasticity genes in at-risk neuronal populations of the aged brain. These novel approaches may help reveal how aging has led to compromise in impulse-flow or synaptic plasticity systems within these populations. We envision that selected aspects of these proposed mechanisms will be testable by evaluation of protein level or function after experimental in vivo manipulations.
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