Combined vitamin D3 and dimethyl fumarate treatment alleviates cognitive dysfunction, oxidative stress, and inflammation in a rat model of sporadic Alzheimer's disease.

Alzheimer's disease (AD) concerns early oxidative and inflammatory disturbances that accelerate tau pathology and cognitive decline. We investigated whether combined treatment with vitamin D3 (VitD3) and dimethyl fumarate (DMF), two agents with complementary antioxidant and immunomodulatory actions, provides additive neuroprotection in the intracerebroventricular streptozotocin (ICV-STZ) rat model of sporadic AD. Male Wistar rats (n = 50) were divided into SHAM, STZ, VITD (STZ + VitD3 2000 IU/kg), DMF (STZ + DMF 50 mg/kg), or COMBO (STZ + VitD3+DMF) groups and treated orally for 90 days. Spatial learning and memory were assessed in the Morris Water Maze. Hippocampal oxidative stress indices (8-isoprostanes (8-Izo)), glutathione (GSH), glutathione disulfide (GSSG), and -SH groups and tau phosphorylation (pTau Ser396) were measured, and circulating vitamin D metabolites quantified by LC-MS/MS. STZ-induced cognitive impairment, elevated lipid peroxidation, increased the GSSG/GSH ratio, and raised pTau in CA1-CA3. VitD3 or DMF each improved acquisition and attenuated the 8-Izo increase; DMF normalized glutathione redox parameters, whereas VitD3 alone decreased GSH despite reducing lipid peroxidation. The COMBO provided the most consistent behavioral improvement and mitigated region-specific pTau elevations while maintaining redox balance. VitD3 treatment increased 25(OH)D3 and 3-epi-25(OH)D3 and reduced the 24,25(OH)2D3/25(OH)D3 ratio, indicating altered vitamin D metabolism. All treated groups showed a decrease in plasma TNF-α. These findings suggest that simultaneous modulation of vitamin D signaling and DMF may synergistically target oxidative, inflammatory, and tau-related mechanisms involved in sporadic AD. Future research should clarify brain-region vitamin D metabolite dynamics and the long-term impacts on protein thiol levels and cognitive function.