Innate immune dysregulation in Alzheimer's disease modeled in Drosophila

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Summary We propose that tau modulates innate immunity and AMPs in the brain, and thereby contributes to progression of Alzheimer’s disease. We will test this idea with Drosophila, where tau dysregulation is produced by a human neurodegeneration-associated mutation introduced into the fly’s endogenous tau, as well as by classic tau over- expression. In both models, tau dysregulation causes age-dependent decline in locomotion and olfaction. Tau over- expression produces neuropathology, and we will assess these traits in our new tau-mutant model. Central to our proposal, we find that expression of genes for innate immunity are dramatically altered in the tau-mutant model. Elevated innate immune expression is a common feature of aging Drosophila, where data demonstrates it contributes to mortality and, potentially, to neurodegeneration. With our observations, we propose that tau dysregulation drives innate immune AMPs to a pathogenic level in the brain of aging Drosophila, causing age-dependent neurodegeneration. In this view, a similar process may well occur in humans that drives the accumulation of Ab. If so, AD might be managed in terms of what drives, regulates and dysregulates innate immunity in the aging brain