Project Summary Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the first cause of dementia. Many lines of genetic and biochemical evidence strongly highlight a pathological role of beta-amyloid (Aβ) where extracellular deposition of amyloid plaques contributes to the loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. As such, the search for disease-modifying therapies for AD has been focused on targeting the hallmark of the disease. Currently, there is no proven pharmacological treatment for preventing the plaques once Aβ forms a larger aggregate and thus there is an urgent need to develop an innovative and alternative strategy to clear Aβ plaques in the AD brain for the treatment of AD. Our long-term goal is to develop a minimally invasive, non-pharmacological intervention to remove toxic Aβ plaques towards the treatment of AD. To this end, herein we propose to apply magnetothermal brain stimulation as a non-pharmacological strategy to target and remove toxic Aβ plaques towards the rescue of Aβ pathology. The principal of this approach is to translate the energy of the high frequency alternating magnetic field (AMF) into thermal energy using superparamagnetic nanoparticles (MNPs) as a transducer that can trigger thermo-mechanical and biological signal with high temporal and spatial specificity. Our central hypothesis is that magnetothermal brain stimulation facilitates Aβ clearance and improves cognitive function via heat shock protein 70 (HSP70) signaling in the AD brain. This hypothesis is based on our published data demonstrating the feasibility of this approach in targeting Aβ plaques where we showed that MNP/AMF-induced thermo-mechanical energy, applied within a safe threshold for brain tissue, was sufficient to direct the disruption of Aβ fibrils into smaller fragments, which were then readily phagocytosed and cleared by microglia. In our preliminary study, we also found that the remotely stimulated thermal energy directed to human microglia could trigger biological signal that shifts microglial activation towards improved Aβ clearance via HSP70-dependent manner. To prove our hypothesis, we propose to (1) establish the threshold safe thermal dose of magnetothermal brain stimulation for brain functioning in mice, (2) develop strategies for targeted magnetothermal brain stimulation towards the improved clearance of Aβ plaques, and (3) investigate the cellular mechanism by which magnetothermal brain stimulation influences Aβ pathology. The successful completion of the proposed study will provide detailed knowledge of how to apply magnetothermal brain stimulation as an innovative therapeutic strategy against Aβ-mediated pathology in AD.