Dimethyl fumarate ameliorates amyloid-beta generated cognitive deficits by inhibiting RIPK1/RIPK3/MLKL necroptosis signalling in rats.

Abstract

Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive dysfunction. Necroptosis plays a pertinent role in the neurobiology of AD, which is governed by receptor-interacting protein kinases (RIPK) and mixed lineage kinase domain-like protein (MLKL). Dimethyl fumarate (DMF), a disease-modifying drug used to treat multiple sclerosis, is also known to inhibit necroptosis pathway. Herein, we examined the effect of DMF in C6 cell line and Aβ1-42-induced AD model. DMF treatment reversed the C6 cell viability and expression of RIPK1, RIPK3, and MLKL in lipopolysaccharide model. Intracerebroventricular injection of Aβ1-42 in rats developed the cognitive deficits. Administration of DMF, at 25 and 50 mg/kg doses via peroral route for 14 days, showed a decrease in escape latency and increased exploration of target quadrant Morris water maze test. DMF-recipient rats also displayed exploration of novel object in novel object recognition test, while locomotor activity remained unchanged in open field test. DMF reduced oxidative processes by decreasing lipid peroxidation and increasing catalase and glutathione. Moreover, DMF treatment decreased the levels of IL-6, TNF-α, and CRP cytokines in frontal cortex. A significant downregulation of RIPK1, RIPK3, and MLKL gene expression and protein expression of p-MLKL were observed in the hippocampus following DMF treatment. DMF was also able to improve synaptic plasticity by increasing the expression of synaptophysin, BDNF, MBP, and PSD95, which were determined by using immunoblot. Our results indicate the cognitive improvement and neuroprotective effects of DMF in Aβ1-42 CE model by modulating the necroptosis signalling. We suggest that the selective targeting of necroptosis process may open new treatment avenues for AD.