Background: T3D-959, a dual PPAR-δ/PPAR γ nuclear receptor agonist and former diabetes drug candidate, has been repositioned as an Alzheimer's disease (AD)-modifying therapy.
Objective: This study examines the effectiveness and mechanisms of T3D-959's therapeutic effects using in vivo and ex vivo rat models of sporadic AD.
Methods: A sporadic AD model was generated by intracerebral (i.c.) administration of streptozotocin (STZ). Control and i.c. STZ treated rats were gavaged with saline or T3D-959 (0.3 to 3.0 mg/kg/day) for 28 days. Spatial learning and memory were evaluated using the Morris water maze test. Frontal lobe slice cultures generated 24 hours after i.c. STZ or vehicle were used to study early effects of T3D-959 (0.5-1.0 μM) on viability and molecular markers of AD.
Results: T3D-959 significantly improved spatial learning and memory in i.c STZ-treated rats. Mechanistically, T3D-959 significantly improved culture viability and brain morphology, reduced levels of oxidative stress and Aβ, and normalized expression of phospho-tau, choline acetyltransferase, and myelin-associated glycoprotein. Protective effects occurred even at the lowest tested dose of T3D-959.
Conclusions: Pre-clinical proof of concept has been demonstrated that T3D-959 can improve multiple pathologies of AD resulting in significant improvements in cognitive function and molecular and biochemical indices of neurodegeneration. These results support the theses that (1) effective disease modification in AD can be achieved by targeting relevant nuclear receptors, and (2) treating AD as a metabolic disease has the potential to be disease remedial. A Phase 2a trial of T3D-959 in mild-to-moderate AD patients has been initiated (ClinicalTrials.gov identifier NCT02560753).
Keywords: Alzheimer’s disease; PPAR agonist; Streptozotocin; T3D-959; Type 3 diabetes; amyloid; slice culture; spatial learning and memory.