AMYLOID PRECURSOR PROTEIN AND ACTIVATION OF MICROGLIA





S.W. Barger*, S-Z. Wu, A.M. Bodles, A.S. Basile

Departments of Geriatrics and Anatomy/Neurobiology, University of Arkansas for Medical Sciences; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA 72205



Alzheimer's disease is associated with inflammatory activation of microglia, but it is unclear whether this contributes to pathology, represents a compensatory response, or both. The beta-amyloid precursor protein (beta-APP) has been implicated in AD by genetics, biochemistry, and cell biology. Derivatives of beta-APP, including amyloid beta-peptide (A-beta) and secreted forms of the amyloid precursor protein (sAPP), can activate an inflammatory phenotype in cultured microglia. Such activation results in production of neurotoxins, which may include reactive oxygen and nitrogen species, cytokines, and excitotoxins. We have been interested in characterizing the relative contributions of such factors to the neurotoxicity exhibited by microglia. Some amelioration of microglial neurotoxicity can be observed with interleukin-1 receptor antagonist. This intervention also attenuates the effects of microglia on other neuronal parameters such as phosphorylation of tau or loss of synaptophysin. However, a larger fraction of the neurotoxicity appears to be mediated by excitotoxins. Antagonists of the NMDA class of glutamate receptor block both increases in calcium and cell death in primary cultures of CNS neurons. A portion of the effect appears to be mediated by glutamate itself, as both sAPP and A-beta stimulate glutamate release from microglia. This release is dependent on the xc- exchange mechanism and thus may result from cellular needs for cystine. Current work is investigating the role of the microglial oxidative burst in creating this cystine “sink.” We have determined that an additional glutamate receptor ligand might also contribute to the excitotoxic consequences of microglial activation. D-serine is an agonist at the glycine site of the NMDA receptor We have determined that A-beta and sAPP stimulate the release of D-serine from activated microglia. This may involve an induction of expression of the synthetic enzyme, serine racemase. Activation of microglia with either A-beta or sAPP elevates serine racemase mRNA, and Alzheimer's disease hippocampus shows elevated levels of serine racemase mRNA. Reporter gene assays of the human racemase promoter suggests that there are transcriptional control elements in the racemase gene that respond to proinflammatory signals. These findings implicate microglia as contributing agents to neuronal pathology in Alzheimer's disease and support the hypothetical involvment of excitotoxic mechanisms in this disorder. Supported by funds from NIA/NIH.




Key words: Alzheimer's disease; glutamate; oxidation; microglia; neurons







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