Altering immune tolerance in Alzheimer disease

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Altering immune tolerance in Alzheimer disease Amyloid plaques composed of deposits of abnormally aggregated amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) consisting of abnormal aggregates of hyperphosphorylated tau protein in the brain are two main pathological changes in patients with Alzheimer’s disease (AD). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased cytokines. The causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular pathways that can modulate the progression of the vast majority of AD cases for development of preventive and therapeutic measures. 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 and inflammatory cytokines, exacerbating Aβ load and causing neurodegeneration. Activating microglia with a beneficial phenotype should have clinically vital importance in AD therapy and prevention. C-type lectin receptors including dectin-1 and toll-like receptors (TLRs) including TLR4 are classes of pattern-recognition receptors in the innate immune system. One of the important roles of these receptors 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 activate microglia, decrease cerebral Aβ deposits and NFTs, and improve cognitive deficits. However, prolonged exposure to certain TLR agonists, such as lipopolysaccharide (LPS), induce hyporesponsiveness to subsequent TLR agonist challenges (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 becomes hypo-responsive to a TLR4 agonist, LPS, after cerebral Aβ deposition (tolerance). Activation of dectin-1 signaling reverses or counteracts LPS tolerance in monocytes. We hypothesize that dectin-1 signaling enhances clearance of Aβ deposits and ameliorates cognitive deficits in an AD mouse model by counteracting and reversing “LPS/Aβ tolerance”. This hypothesis will be tested by carrying out the following aims. In Aim 1, we will produce a dectin-1-deficient (clec7a-/-) AD mouse model and determine its effects on AD-pathology and behavioral functions. In Aim 2, we will inject a dectin-1 ligand into the hippocampi of dectin-1-deficient and -sufficient AD mouse models and determine its effects on AD pathology and behavioral functions. The long term goals of this study are to determine the role of dectin-1 signaling in the AD pathogenesis and to develop new preventive and therapeutic strategies for AD.