Alzheimer's disease (AD), a neurodegenerative disorder characterized by neuronal and synaptic loss, brain atrophy and slow, progressive dementia remains a major unmet medical need. Despite decades of research, a cure remains elusive and treatment options are limited (1). In 2015, approximately 5.3 million US citizens have AD and the cost of patient care is staggering. The direct cost of AD patient care in the US is ~$226 billion, and nearly half of this cost is borne by Medicare. In the absence of novel therapies, the US AD patient population is expected to exceed 13.8 million by 2050 and the cost of care will balloon to over $1.1 trillion. Glutamate is a key compound in the brain that is important for memory and learning, its concentration are regulated in part by glutamate transporter (GLT-1). We have discovered a new compound, MC-100093, that has the ability to increasing GLT-1 levels in the brain. In this program, we will explore the potential utility of Glutamate Transporter-1 (GLT-1) expression enhancers as a novel approach for the treatment of AD. We will assess tool compounds and new compounds to be designed and synthesized for their activity in AD animal models. The GLT-1 enhancement approach is substantially different from other mechanisms of action currently under investigation, as it does not directly target Aβ production. More importantly, our lead compound has shown efficacy in animal models of cerebral palsy through its enhancing activity on GLT-1 expression and resulting increase in glutamate re-uptake. This class of novel compounds has the potential to ameliorate the memory deficits and brain lesions in AD model. Positive results would pave the way for the development of this compound class as novel therapies for AD.