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Project Topic
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Alzheimer’s disease (AD) is the main cause of dementia in the aging population affecting disproportionately more women than men (2:1). However, the cellular, molecular and pathogenic mechanisms underlying sex differences in the risk and progression of AD are still unknown, despite the fact that they should be considered when developing personalized strategies for precise diagnosis and therapies. Sex-differences in cognition and emotion in adults were recently associated to changes in parvalbumin (PV) interneurons, the most abundant inhibitory neurons that control hippocampal excitatory/inhibitory balance and gamma oscillations in the brain. Importantly, we and others have recently shown that hippocampal PV interneurons comprise an early vulnerable neuronal population implicated in excitatory/inhibitory imbalance and memory impairment in AD. However, the molecular mechanisms underlying dysfunction, degeneration and altered pathways of PV interneurons at pre-symptomatic and early stages of AD are still unknown. The HYPOTHESIS of this project is that early transcriptional, functional and synaptic changes in PV interneurons cause excitatory/inhibitory imbalance and dysfunction of memory neural circuits contributing to early sex-specific vulnerability in AD. The AIMS of this collaborative project are: 1) to identify gene signatures and cellular pathways underlying structural and functional changes of PV interneurons associated with early sex-specific vulnerability in AD, 2) to modulate the activity and molecular mechanisms of PV interneurons to rescue synapse function, excitability and memory in well-established AD mouse models and human AD iPSCs-derived interneurons, and 3) to identify novel PV biomarkers differentially affected by sex for early diagnosis and measurement of AD progression. To achieve these goals, we will apply state-of-the-art multidisciplinary and integrative experimental approaches, including single-cell and cell-specific transcriptomics, cerebral electrophysiological recordings, chemogenetics and CRISPR-mediated gene editing in AD mice and iPSC-derived neurons from AD patients, as well as integration of experimental and clinical data on transcriptomics and biomarkers in two well-established longitudinal AD human cohorts (ROSMAP and SPIN).
Our consortium composed of leading experts in clinical and experimental research in AD and neurodegeneration, plus an external collaborator (Philip De Jager, Columbia University) with access and expertise in transcriptomic analysis of the ROSMAP AD cohort, is well positioned to lead this translational project because it holds multidisciplinary expertise in neuropathology, neurobiology, neurology, physiology, behavior, transcriptomics, and bioinformatic/artificial intelligence. Importantly, this project will provide novel mechanistic insights on PV interneuron gene networks, molecular pathways and physiology linked to sex-dependent vulnerability in AD. By advancing in the discovery of novel fluid PV biomarkers, in combination with well-established ones plus cognitive, social, and clinical measures of two well-characterized AD cohorts, we aim to develop accurate diagnostic tools for monitoring disease progression at early AD stages. In summary, a better understanding of sex-specific AD risk and protective factors is critical for developing individualized interventions for the prevention and treatment of AD.
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