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 phosphotau, 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).

Both alcohol and NNK exposures contribute to ALD pathogenesis, including insulin/IGF resistance and inflammation. The differential effects of EtOH and NNK on adduct formation are critical to ALD progression among alcoholics who smoke.

Background Meta-analysis studies showed that smokers have increased risk for developing Alzheimer’s disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity. Objective The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions. Methods Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis. Results Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated. Conclusion CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.