Mast cells (MCs) play important roles in allergic responses. Recent studies suggest that MCs are also essential to other inflammatory diseases by releasing inflammatory cytokines, chemokines, and the MC- specific proteases chymase and tryptase after degranulation. Pharmacological inactivation of MCs prevents or slows disease progression. Alzheimer’s disease (AD) is the most common cause of dementia and disability in the elderly. It is the sixth leading cause of death in the U.S., affecting more than 5 million Americans alone, according to the Alzheimer’s Association. One definitive diagnosis of AD is based on the presence of extracellular deposition of neurotoxic β-amyloid (Aβ) into senile plaques. Human AD brains have elevated protease expression, neuronal death and synapse loss, blood-brain barrier (BBB) leakage, and activation of inflammatory cells such as microglia, astrocytes, and T cells. MCs also present in human AD brains, mainly in the hippocampus, cerebral cortex, and thalamus, but studies have yet to test whether these cells participate directly in the pathogenesis or serve merely as another inflammatory hallmark. Our preliminary data demonstrated that the plasma levels of MC activator IgE and MC granular contents tryptase and histamine were elevated in patients with early stage AD, indicating enhanced systemic MC activation. Anti-tryptase and CD117 antibodies detected MC accumulation in the cortex and hippocampus from human and murine AD brains. Using MC-deficient KitW-sh/W-sh mice and over-the-counter (OTC) MC inhibitor ketotifen, we demonstrated that the absence or pharmacological inhibition of MCs reduced Aβ deposition and senile plaque formation in the hippocampus and cerebral cortex, and reduced the numbers of total Iba-1-positive microglia and CD68-positive phagocytic microglia in these regions in APPSWE-PS1∆e9+/– (APP-PS1) mice that develop cerebral amyloidosis. Brain tissue extract ELISA showed that the absence of MCs reduced the production of pathological Aβ species (Aβ1-40 and Aβ1-42). Adoptive transfer of in vitro-prepared MCs into KitW-sh/W-shAPP-PS1- recipient mice restored cortical and hippocampal Aβ deposition, microglia infiltration and activation, and AD brain cortex Aβ1-40 and Aβ1-42 contents. A preliminary water T-maze behavior test suggested that MC depletion improved cognitive decline in APP-PS1 mice. We hypothesize that MCs play a pathogenic role in AD by releasing pro-inflammatory cytokines and proteases, and MC inhibition with the anti-allergy drugs may become a novel therapy of human AD. We propose three aims to examine whether MC depletion or inhibition protects mice from Alzheimer’s disease; to examine whether genetic deficiency of FcεR1 or anti-IgE antibody therapy protects mice from Alzheimer’s disease and, to establish the mechanistic link between mast cell activation and mouse Alzheimer’s disease.