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Alzheimer’s disease (AD) is an incurable neurodegenerative disease and the most common cause of dementia worldwide. AD is caused by the slow aggregation of the amyloid (A) protein into amyloid plaques across the entire brain. Previous medical interventions for AD have focused on breaking apart amyloid plaques into smaller pieces which can be degraded by microglia phagocytosis and degradation in lysosomes. However, emerging evidence suggests that A proteins and plaques evade degradation within microglial lysosomes by inhibiting lysosome acidification. Lysosome acidification is necessary for the activation of lysosomal proteases which are capable of degrading A. Therefore, restoring microglial lysosome acidification is a potential therapy for AD. In this proposal, we introduce AzLAN, an acidifying nanoparticle targeted to amyloid plaques, which can potentially restore microglial lysosome acidification and reverse AD-caused dementia. We propose to test AzLAN’s efficacy in both in vitro and in vivo models of AD. Our innovative technical approach in the creation of AzLAN will allow the nanoparticle to recognize A fibrils, target A to microglial lysosomes and restore microglial lysosomal acidification. We propose to test AzLAN’s therapeutic efficacy through both in vitro and in vivo models of AD. First, we will verify AzLAN’s ability to recognize A and become a target of microglial phagocytosis. Second, we will test if AzLAN can restore microglial acidification in culture models of AD. Third, we will verify the ability of AzLAN to cross the Blood-brain barrier, a major obstacle in delivering therapeutics to the brain. Fourth, we will test to what degree AzLAN treatment protects cognitive function in mouse behavioral models of AD dementia. Finally, we will investigate AzLAN’s ability to reduce A plaque size and number through immunohistochemical staining. Our conceptually innovative approach to treating AD by restoring microglial lysosome acidification through AzLAN will deliver an effective therapeutic option for AD patients.
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