PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia characterized by neuronal loss and synaptic dysfunction, and histopathologically hallmarked by the presence of amyloid plaques and neurofibrillary tangles. The correlation between histopathology and dementia has been challenged in the past decade by the emergence of a group of individuals who remain cognitively intact despite the presence of plaques and tangles consistent with clinically symptomatic AD. The existence of these individuals, here referred to as Non-Demented with AD Neuropathology (NDAN) suggests that there is a natural way for the human brain to escape dementia. Understanding the underlying molecular and cellular mechanisms of resilience (the main objective of the present project) may help the development of innovative treatment concepts based on inducing cognitive resilience in anyone challenged by AD neuropathology. We present compelling preliminary results that support our hypothesis that efficient TREM2-driven microglial phagocytosis underlies structural integrity and functionality of synapses in NDAN, thus protecting from ensuing cognitive deficits. We will test our central hypothesis by pursuing the following specific aims: testing whether high expression levels of microglial TREM2 are associated with phagocytosis of damaged synapses around amyloid plaques in NDAN subjects, and evaluating the presence of variants of TREM2 gene in NDAN subjects as a function of synaptic resilience. This present project is highly significant because the proposed studies will establish TREM2 phagocytic microglia as a key player in the maintenance of synaptic integrity. The successful completion of the aims will provide insight into molecular and cellular mechanisms underlying synaptic resilience in relation to microglia activity in NDAN individuals revealing new targets for future development of innovative treatment concepts based on inducing cognitive resilience in individuals challenged by AD neuropathology. The proposed project will improve our scientific understanding of how damaged synapses removal is mediated by TREM2 phagocytic microglia contributing to synaptic integrity in NDAN.

PROJECT NARRATIVE The proposed research is relevant to public health because of the positive impact that the discovery of mechanisms underlying synaptic integrity in resilient individuals will reveal novel therapeutic concept centered on inducing resilience and extend this novel concept to related disorders that share with AD the pathological disruption of synapses. The proposed research is aligned to NIH’s mission of fostering creative discoveries to protect and improve health.