Project Summary / Abstract Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD) are the most common neurodegenerative disorders that lead to dementia in millions of patients. The number of people affected by these diseases and the corresponding cost to society is predicted to double within 20 years. To develop effective therapies, new biomedical approaches, concepts, and molecular targets are critically needed. The discovery of a novel class of molecular regulators called microRNA (miRNA) has revolutionized biology and is predicted to have a major impact on medicine. miRNAs, the small non-protein-coding RNAs, post-transcriptionally regulate gene expression in various physiological and pathological conditions. Accumulating evidence suggests that dysregulated miRNA signaling plays an important role in several neurodegenerative diseases, including AD and FTD. A specific miRNA, miR-132, previously implicated in neuronal development, plasticity, and viability, has recently emerged as the most significantly down-regulated in the early stages of AD, as well as FTD and PSP. It is associated with the AD pathology, including both amyloid plaques and tau-formed neurofibrillary tangles. Our data suggest that miR-132 protects neurons against disease-related toxins such as Ab and glutamate and that its replacement might be neuroprotective in the brain. Many genes associated with tau metabolism, as well as those antagonizing neuronal apoptotic machinery, have been predicted as direct miR- 132 targets. Nevertheless, the molecular mechanism underlying the neuroprotective properties of miR-132, as well as the genetic and physiologic context of its neuroprotection, is unknown. The overall goal of this project is to dissect miR-132 signaling, define its role in AD and FTD neurons, and investigate neuroprotective properties of this miRNA in human cells and mouse models of amyloid and tau-induced neurodegeneration. To achieve this goal, we propose three Specific Aims. Specific Aim 1 will define the commonality and genetic constraints of miR-132-mediated signaling and neuroprotection. Using neurons differentiated from a panel of iPSC lines from controls, AD and FTD patients, we will unravel miR-132 signaling, its primary targets contributing to distinct paths to neurodegeneration and disease, and define the links between miR-132 activity, tau and amyloid pathology, and neuronal vulnerability and death. Specific Aim 2 will develop pre-clinical metabolically stabilized compounds for the investigation of sustained miR-132 replacement in the brain in vivo. Specific Aim 3 will investigate the mechanisms of miR-132 neuroprotection in two distinct mouse models o...