Requirements of a brain selective estrogen: advances and remaining challenges for developing a NeuroSERM

Abstract

Our goal is to develop therapeutic agents that prevent age-associated neurodegenerative disease such as Alzheimer's. To achieve this goal, we are building on extensive knowledge regarding mechanisms of estrogen action in brain and the epidemiological human data indicating that estrogen/hormone therapy reduces the risk of developing Alzheimer's disease when administered at the time of the menopause and continued over several to many years. The mechanisms of estrogen action in neurons provides a systematic mechanistic rationale for determining why estrogen therapy is efficacious for prevention of Alzheimer's disease and why it is not efficacious for long-term treatment of the disease. Our preclinical research plan is a hybrid of both discovery and translational research to develop a brain selective estrogen receptor modulator (SERM). We have termed such molecules NeuroSERMs to denote their preferential selectivity for activating estrogen mechanisms in brain. Our strategy to develop NeuroSERMs is threefold: (1) determine the target of estrogen action in brain, specifically the estrogen receptor in hippocampal and cortical neurons required for the neurotrophic and neuroprotective actions of estrogen; (2) develop NeuroSERM candidate molecules using three in silico discovery and design strategies and (3) determine the neurotrophic and neuroprotective efficacy of candidate molecules using neuronal responses predictive of clinical efficacy. Using an academic translational research model, a team of scientists with expertise in molecular biology, computational chemistry, synthetic chemistry, proteomics, neurobiology and mitochondrial function have been assembled along with state of the art technologies required to develop candidate NeuroSERM molecules.