Alzheimer's Disease (AD) is a progressive, neurodegenerative disease characterized by gradual cognitive decline and memory loss. Although research has focused on elucidating the risk factors, pathophysiologic abnormalities associated with AD and on mechanisms of impeding disease progression, results indicate that a variety of factors may contribute to AD which makes treating this disease difficult. The neuropathological hallmarks of AD include senile plaques which are composed of extracellular

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... eposits of amyloid beta (Aβ) peptide as well as neurofibrillary tangles, neuronal loss and inflammation. Microglia, the immune cells of the CNS, are abundantly found in the vicinity of neuritic plaques. It is believed that microglia become activated in response to Aβ leading to an inflammatory response and subsequent neuronal loss associated with AD pathogenesis. Modulation of the Aβ-induced intracellular signaling and functional responses of microglia could serve as a therapeutic strategy for AD. Full length amyloid beta, Aβ₁₋₄₂, induced distinct intracellular signaling pathways in human microglia. Electophysiological studies indicated that Aβ₁₋₄₂ acutely applied to human microglia upregulated the expression of a novel outward K⁺ current, sensitive to the nonselective K⁺ channel blocker 4-aminopyridine (4-AP). A similar outward K⁺ current was activated by intracellular application of GTPγS which suggests that Aβ₁₋₄₂ induces an outward K⁺ current in microglia via a G protein. Molecular biology studies indicated that the K⁺ channel upregulated by Aβ₁₋₄₂ was likely due to Kv3.1. Aβ₁₋₄₂ also caused a transient depolarization of microglia and increased the expression of the FcγII receptor. The FcγII receptor mediated this depolarization since antibody inhibition of the FcγII receptor inhibited the Aβ₁₋₄₂-induced depolarization. In addition to its ability to block the outward K⁺ current upregulated by Aβ₁₋₄₂, several in vitro and in vivo assays indicated that 4-AP modulates Aβ₁₋₄₂-induced intracellular signaling and f [...]