S1‐03–02: Liver X Receptors act to facilitate Aβ clearance and suppress inflammation in the Alzheimer's disease brain

genetic manipulations: reduction of endogenous tau or apoE, and/or expression of human apoE3 or apoE4 in neurons or astrocytes. Mice of the resulting genotypes were analyzed with a variety of behavioral, electrophysiological, biochemical, and histological methods. Results: APP mice showed age-dependent deficits in learning and memory, other behavioral changes, synaptic deficits, nonconvulsive epileptiform activity, informative alterations in synaptic activity-related biomarkers, and premature mortality. These abnormalities correlated well with forebrain levels of specific A oligomers, but not with plaque loads. Notably, most of the abnormalities were effectively prevented by reduction of tau and were worse in hAPP/apoE4 mice than in hAPP/apoE3 mice, independent of differences in plaque formation. Even partial tau reduction effectively blocked A -induced cognitive and neuronal dysfunction without changing plaque burdens or A oligomer levels. It also made mice without hAPP more resistant to chemically-induced epileptic seizures. In contrast, neuronal expression of apoE4 made mice more susceptible to neuronal damage inflicted by such seizures compared with mice expressing apoE3 or no apoE at all. Conclusions: These results shed light on the intriguing link between AD and epilepsy and suggest novel roles for tau and apoE4 in excitotoxicity. Because aberrant neuronal excitation likely contributes to diverse neurological diseases, our findings may have broad therapeutic implications.