Microglia and Tau Oligomer Polymorphs Interplay in Cognitive Resilience in Alzheimers disease - PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common and severe form of neurodegenerative disorder, affecting nearly 50 million people worldwide, for which there is still no resolving cure. Identifying novel, effective therapeutic strategies for AD is therefore urgent. The existence of individuals who remain cognitively intact despite the presence of histopathological signs of AD, here referred to as “Non demented with AD neuropathology” (NDAN), suggests the existence of innate protective mechanisms opposing the events that normally lead to cognitive impairment. Neuroinflammation and various activated microglia phenotypes are frequently seen in neurodegenerative diseases, with microglia playing a pivotal player. Specifically, the involvement of the microglia-associated transmembrane receptor TREM2 in Aβ and tau pathologies has been documented in AD and related disorders, where highly phagocytic TREM2-expressing microglia play key roles in pathological outcomes. Within this critically needed knowledge, the relationship between unique tau oligomer polymorphs associated with resilience and specific phenotypes of activated microglia remains uncharted; obtaining such new knowledge is key to develop specific, effective therapies centered on inducing resilience. We here present compelling preliminary results that support our central hypothesis that Brain Derived Tau Oligomer (BDTO) isolated from NDAN brains (NDAN-BTDO) exhibit reduced toxicity as compared to AD-BDTO and induce a distinct microglial phenotype, triggering a specific inflammatory response associated with resilience. We will test our central hypothesis by pursuing the following specific aims: Specific Aim 1. To test the hypothesis that NDAN-BDTO are less toxic than AD-BDTO and elicit the activation of phagocytic microglia that differentially affect synapse function. Specific Aim 2. To test the hypothesis that treatment with TREM2-activating antibody is protective vs. AD BDTO, increasing microglia phagocytosis and reducing BDTOs toxic effects. Once the present project is successfully completed our expectation is that we will have identified specific microglia phenotypes and their transcriptome signature driven by BDTO unique to resilience. We will learn selective pathways and elements associated with specific impact of the NDAN-BDTO polymorphs driving inflammatory microglia that will reveal novel treatment targets centered on inducing resilience.
