AGING AND THE NEURONAL CYTOSKELETON

越来越多的证据暗示神经元钙的失调

Accumulating evidence implicates dysregulation of neuronal calcium homeostasis contributing both to age-related cognitive deficits and to increased vulnerability of neurons to degeneration. Recently, rat brain hippocampal neurons were shown to exhibit a dramatic age- related increase in the activity of L-type voltage-sensitive calcium channels, suggesting that calcium entry through such channels may alter normal synaptic signaling mechanisms in neurons. This pilot project seeks to examine the contribution of L-type channels to regulation of the postsynaptic cytoskeletal protein MAP2. Previous studies have shown that the phosphorylation state of MAP2 is regulated by calcium-dependent signaling pathways, including calcium-dependent protein phosphatases. This project therefore will test the hypothesis that aged hippocampus is more susceptible to calcium-dependent activation of protein phosphatases that target MAP2. Alterations in phosphorylation state are one of the primary ways in which the structure and function of proteins are regulated, and such structural changes may differ in the aged brain as compared to the young adult. Several lines of evidence suggest that protein phosphatases are logical subjects of investigation in the context of normal aging. Furthermore, MAP2 is a postsynaptic cytoskeletal protein that is regulated by neural activity and is hypothesized to help control the balance between plasticity and stability of neuronal dendrites. These studies, therefore, are generally relevant to understanding mechanisms of cytoskeletal regulation that may go awry in degenerative diseases of aging. In addition, they will contribute to our understanding of mechanisms regulating protein structure during normal aging.