Modulation of innate immunity in Alzheimer disease Patients with Alzheimer?s disease (AD) develop deposits of abnormally aggregated amyloid ?-protein (A?) and abnormal aggregates (neurofibrillary tangles, NFTs) of hyperphosphorylated tau protein. Fibrillar A? 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 A? deposits by phagocytosis and promoting neuron survival and plasticity or releasing cytotoxic chemicals, inflammatory cytokines, exacerbating A? load and neurodegeneration. Activating microglia with a beneficial phenotype should have clinically vital importance in AD therapy and prevention. A? 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 A?. Indeed, treatments of AD mouse models with certain TLR agonists activates microglia and decreases cerebral A? 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 A? aggregates are a TLR agonist, we hypothesize that chronic exposure of microglia to A? aggregates induces A?/TLR tolerance, leading to decreased clearance of A? 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 A? deposition (a primed, hypersensitive state) but hypo-responsive after cerebral A? deposition (tolerance). We found that certain biomarkers of TLR tolerance are upregulated in an AD mouse model after the development of A? deposition in the brain. Multiple immunomodulators can reverse LPS tolerance in monocytes. We hypothesize that such immunomodulators enhance clearance of A? deposits and ameliorate cognitive deficits in an AD mouse model (Aim 1) by reversing ?LPS/A? 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 A?/TLR tolerance induced by A? deposition can be reversed by certain immunomodulators leading to amelioration of AD-like pathophysiology. If successful, this study will offer a new immunotherapeutic approach for AD.
The etiology of Alzheimer?s disease (AD) is unknown and satisfactory treatments for AD are unavailable. We hypothesize that accumulation of amyloid protein found in the AD brain induces microglial dysfunction, leading to dementia, and that certain immunomodulators enhance clearance of A? deposits and ameliorate cognitive deficits in an AD mouse model by restoring microglial functions. This study will serve as a proof of principle to determine if microglial dysfunction can be reversed by certain immunomodulators, leading to amelioration of AD- like pathophysiology in an AD animal model.
