The goal of this proposal is to develop tumor necrosis factor ? (TNF?)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer's disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-? as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNF? is a "druggable" molecular target to modify the course of AD progression. P2D, inc. is developing a novel TNF? inhibitor, PD2015 (3,6'dithiothalidomide), a dithionylated analog of thalidomide as an anti-AD drug candidate for in vivo efficacy testing in a mouse model of AD. PD2015 exhibits 1800% greater TNF? inhibition in vitro than its parent, thalidomide. The applicant organization recently published work demonstrating the efficacy of PD2015 in 3xTg AD mice . A 50 mg/kg PD2015 i.p. dose administered daily for two months significantly improved working memory (*P<0.05) in 3xTg AD mice. PD2015 also significantly modulated brain TNF? levels after daily treatment for two months in 3 x Tg AD mice. Recent preliminary studies with chronic oral PD2015 dosing (50 mg/kg) demonstrate improved cognition. In contrast, thalidomide did not improve working memory or block brain TNF? levels in 3 xTg AD mice. Taken together, these data strongly suggest that PD2015 is a good anti-AD drug candidate. The proposed preclinical study is designed to evaluate the oral efficacy of chronic low doses of PD2015 administration across a 12-fold dose range in symptomatic 6 mo. old 3xTg AD mice.
Specific Aim 1 A): Determine the effect of chronic oral administration of PD2015 on cognitive function in 3xTg AD mice.
Specific Aim 1 B): Determine the effect of PD2015 on indicators of neuroinflammation and AD- associated pathology including TNF-? levels, Ass1-40/Ass1-42 levels, microglial activation, tau, phospho-tau, synaptophysin, SNAP-25 in 3xTg AD mice.
Alzheimer's Disease (AD) is a significant neurological problem affecting 4.5 million of our senior U.S. citizens. The present research aims to develop an effective drug that can be taken orally to target the underlying neuroinflammation in AD to modify disease progression and improve cognitive function and block the underlying AD-associated pathology.