Project Summary/Abstract Alzheimer’s disease (AD) is a major neurodegenerative disease affecting millions of people with no cure. There is an urgent need to identify potential causes and mediators that may contribute to AD onset to advance preventive strategy. Emerging evidence suggested that epigenetic regulation of gene expression in human neurons is a major mechanism in AD pathogenesis. Protein Arginine Methyltransferase 5 (PRMT5) has been recognized as a critical epigenetic regulator that transmits extracellular signaling (e.g., stress) into gene expression. High PRMT5 expression is found in human neurons, whereas PRMT5 expression is decreased in AD patients. Knockdown of PRMT5 significantly increases apoptosis of neuronal cell lines over-expressing the AD-related Swedish mutation of the human amyloid-β precursor protein. We have observed, under the current R01 support, that PRMT5 is required for the survival of NE-like cells, a neuron-like cancer cells in prostate cancer. Given that PRMT5 has emerged as an oncogene and that targeting PRMT5 with small molecule inhibitors for the treatment of several human cancers is in clinical trials, it is critically important to define the role of PRMT5 in human neurons to prevent treatment-induced damages to neurons and the development of AD-like dementia. In this proposed study, Hu and Yang lab take advantage of neurons derived from healthy and AD human induced pluripotent stem cells (hiPSCs) carrying AD susceptible genetic risk factors to tackle this problem. We hypothesize that PRMT5 provides a survival signal in NE-like cells and human neurons via epigenetic regulation of its target gene expression and that reduced expression/activity of PRMT5 in neurons leads to neuronal death and development of AD phenotypes. We will test this hypothesis with the following aims. Aim 1. To elucidate the protective role of PRMT5 in NE-like cells and human AD neurons via epigenetic regulation of gene expression. By completion of this aim, we will gain a deep understanding of the shared and distinct protective roles of PRMT5 in NE-like cells vs in neurons carrying AD susceptible genetic risk factors. Aim 2. To determine the tolerability of human healthy and AD neurons in responses to PRMT5 inhibition. Findings from this aim may provide evidence that targeting PRMT5 for cancer treatment would cause potential toxicities to human neurons and the development of AD-related neuropathology. The results obtained from this Administrative Supplement will provide knowledge regarding how PRMT5 serves a shared or distinct protective role in NE-like cells and neurons carrying AD genetic risk factors to halt the neurotoxicity of AD. Our study evaluates the consequences of PRMT5 inhibition/knockdown on healthy and AD neurons carrying AD genetic risk factors, shedding light on strategies to prevent PRMT5-based cancer therapeutics-related impairment of neurocognitive functions including AD-like dementia.