Lay Summary Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Currently, about 6.5 million Americans are living with AD. Alzheimer’s and other dementias are estimated to cost the US $321 billion per year and this number is expected to 1 trillion by 2050, yet no small molecule therapeutic agent on the horizon that clearly alters the disease progression and inevitable cognitive decline. The small molecule drugs and anti-bodies that have been developed based on the amyloid cascade hypothesis showed a limited (if any) disease modifying benefit so far. Thus, it would be very important to validate novel drug targets and small molecules that work through a novel mechanism of action for future AD therapy. Neuroinflammation is recognized as a key phenotype in the AD brain that is associated with the development of dementia. Prostaglandin-E2 receptor EP2, which acts downstream of complex signaling by cyclooxygenase-2 (COX-2) appears as a key driver of neuroinflammation. Activation of this receptor further induces COX-2 creating a vicious reactive cycle in the brain. We have recently developed a suite of small-molecule antagonists for this receptor and derived a proof-of-concept in 5xFAD mouse models demonstrating antagonism of EP2 attenuates neuroinflammation and the amyloid load in the brain. Moreover, we have validated that EP2 receptor antagonism is associated with cognition sparing benefits in acute brain injury models of status epilepticus and a peripheral inflammatory sepsis model. We have identified several preclinical lead candidates for development into a clinical lead and candidate drug to mitigate neuroinflammation and cognitive deficits in Alzheimer’s patients. We now propose to define PK/PD relations of the lead EP2 antagonists on Alzheimer’s pathology markers in the brain and determine PK/PD relation on the AD relevant biomarkers in the blood (plasma), CSF and the brain tissue in two different mouse (5xFAD and APPSAA) models that that display features of early-onset of AD (EOAD) and late-onset of AD (LOAD) in human. Furthermore, we proposed to conduct drug development studies to determine therapeutic index and NOAEL for the lead EP2 antagonist and complete all other IND-enabling studies required by the FDA. Our overall goal is to achieve a disease modifying efficacy by the EP2 drug that delays the progression of Alzheimer’s dementia at least by 5 years. We envision that targeting EP2, a specific prostanoid receptor downstream of COX-2, rather than a generic block of the entire COX-2 signaling is a superior therapeutic strategy for AD that will bypass the adverse cardiovascular events found with chronic dosing of COX-2 drugs.

Narrative Alzheimer’s disease is associated with a substantial medical and societal burden, but no small molecule therapy that alters the disease progression is currently available. Several studies including our own indicate that prostaglandin-E2 receptor EP2 is associated with exacerbation of inflammation and neurodegenerative pathology and cognitive deficits in rodent models of Alzheimer’s disease. We propose to develop an EP2 inhibitor with an overall goal to suppress neuropathology and cognitive deficits in mouse models and eventually in human patients with Alzheimer’s disease.