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.