Modulation of innate immunity in Alzheimer disease Patients with Alzheimer’s disease (AD) develop deposits of abnormally aggregated amyloid β-protein (Aβ) and abnormal aggregates (neurofibrillary tangles, NFTs) of hyperphosphorylated tau protein. Fibrillar Aβ deposits in the brain are accompanied with activated microglia. Many lines of evidence support the notion that activated microglia, innate immune cells in the central nervous system, play pivotal, dual roles in AD progression: either clearing Aβ deposits by phagocytosis and promoting neuron survival and plasticity or releasing cytotoxic chemicals, inflammatory cytokines, exacerbating Aβ load and neurodegeneration. Activating microglia with a beneficial phenotype should have clinically vital importance in AD therapy and prevention. Aβ aggregates activate microglia through certain toll-like receptors (TLRs) including TLR4. TLRs are a class of pattern- recognition receptors in the innate immune system. One of the important roles of TLRs is to activate microglia in response to pathogens and damaged host cells, and to clear pathogens, damaged tissues, and accumulated wastes. Activation of microglia through certain TLRs can markedly boost ingestion and clearance of Aβ. Indeed, treatments of AD mouse models with certain TLR agonists activates microglia and decreases cerebral Aβ deposits, NFTs and improve cognitive deficits. However, prolonged exposure to certain TLR agonists, such as lipopolysaccharide (LPS), induce hyporesponsiveness to subsequent TLR agonist challenge (endotoxin/TLR tolerance), leading to immune paralysis. Because Aβ aggregates are a TLR agonist, we hypothesize that chronic exposure of microglia to Aβ aggregates induces Aβ/TLR tolerance, leading to decreased clearance of Aβ aggregates and reduced neuronal survival and plasticity in AD and its animal models. We found that an AD mouse model is hyper-responsive to a TLR4 agonist, LPS, prior to cerebral Aβ deposition (a primed, hypersensitive state) but hypo-responsive after cerebral Aβ deposition (tolerance). We found that certain biomarkers of TLR tolerance are upregulated in an AD mouse model after the development of Aβ deposition in the brain. Multiple immunomodulators can reverse LPS tolerance in monocytes. We hypothesize that such immunomodulators enhance clearance of Aβ deposits and ameliorate cognitive deficits in an AD mouse model (Aim 1) by reversing “LPS/Aβ tolerance” (Aim 2). This hypothesis will be tested by carrying out the following specific aims: (Aim 1) to investigate the effects of an immunomodulator on AD-like pathology and cognitive functions in an AD mouse model and (Aim 2) to investigate the effect of an immunomodulator on reversing LPS tolerance. This study will serve as a proof of principle to determine if Aβ/TLR tolerance induced by Aβ deposition can be reversed by certain immunomodulators leading to amelioration of AD-like pathophysiology. If successful, this study will offer a new immunotherapeutic approach...