Investigating Aberrant Neuronal Calcium Signalling In Alzheimers Disease

Substantial evidence indicates that aberrant neuronal Ca2+ regulation may contribute to the pathogenesis of Alzheimer's disease (AD). The aim of this thesis was to further investigate cellular events associated with elevated neuronal Ca2+ in AD. Proteins altered by increased Ca2+ concentration were assessed in post-mortem neurodegenerative disease brain. Increased amounts of active calpain-1 and decreased amounts of active calpastatin, an endogenous calpain inhibitor, were found in AD brain in comparison to control tissue. In addition, elevated calpain-mediated cleavage of several proteins was found in AD brain, including that of the sodium calcium exchanger (NCX3), which normally acts to extrude excess cellular Ca2+. Mechanisms that contribute to increases in neuronal Ca2+ concentration in AD were identified using a primary culture model of AD. Application of oligomeric A[beta] 1-42 to cells was shown to increase the activity of calpains, caspase-3 and induce tau phosphorylation and cleavage through a pathway dependent upon poly-ADP ribose mediated gating of transient receptor potential cation channel, melatonin subfamily 2 (TRPM2) channels. Finally, to begin to examine the potential role of selected neuronal Ca2+ sensors (NCS) in AD, their expression and distribution was examined in primary neurons under different conditions, and in postmortem AD brain. Decreases in the amounts of two of these proteins, DREAM and hippocalcin, were apparent following A[beta] treatment of primary cortical cultures, and A[beta]-induced a Ca2+-dependent relocalisation of hippocalcin within cells, a phenomenon believed to alter the function of this protein. Therefore, these results may suggest that alterations in NCS proteins influence the response of neurons to A[beta]-induced increases in cellular Ca2+ concentration.