Transgenic mice, inflammation & the Alzheimer phenotype

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Inflammation is increasingly viewed as the pathogenic mechanism in Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) associated with reduced risk of AD reduce Abeta load in a transgenic mouse model of amyloid deposition. Vaccination with Abeta also reduces Abeta load and protects transgenic mice from memory deficits, but activates microglia, a sign of inflammation. We report here that treatment of transgenic mice with a modified NSAID can also reduce Abeta load and activate microglia in an APP+PSI doubly transgenic mouse model of amyloid deposition. This application will test whether the vaccination and modified NSAID approaches are additive saturable or counteract each other with respect to amyloid removal, learning and memory and/or gene expression changes known to occur in these transgenic animals. We will also determine which components of the modified NSAID are critical for the microglial activation and amyloid reducing effects of the compound. We will compare the ability of a range of anti-inflammatory agents, working via different mechanisms, to modify microglial activation and Abeta load in transgenic mice injected with lipopolysaccharide or injected with anti- Abeta antibodies. Because these two agents activate microglia by different mechanisms, we hope to clarify which anti-inflammatory drugs might be useful to consider in conjunction with potential vaccine therapies for AD. Finally, we will determine a subset of genes modified in the doubly transgenic mice that are concomitants of amyloid deposition and, possibly, memory dysfunction, as opposed to genes which are modified by aging or transgene overexpression.