Intermittent treatment with Apremilast, a phosphodiesterase-4 inhibitor, ameliorates Alzheimer's-like pathology and symptoms through multiple targeting actions in aged T2D rats

[Display omitted] •HF/HFr/l-STZ induced T2D and cognitive impairment in aged rats which were reversed by Apre.•Apre significantly reduced hippocampal degenerative cells, tau-positive cells, elevated Aβ levels, ChE activity and caspase-3 activity,•Apre suppresses down regulation of hippocampal gene expression of AMPA and NMDA glutamate receptor subunits.•These improvements may be attributed to decreased pro-inflammatory cytokines, oxidative insulin resistance, and GSK-3 level. Apremilast (Apre), a novel phosphodiesterase-4 (PDE4) inhibitor, has been shown to have anti-inflammatory, immunomodulator, neuroprotective and senolytic properties, therefore, Apre like other PDE4 inhibitors may be a promising candidate for treatment of Alzheimer's disease (AD). To evaluate the effectiveness of Apre on Alzheimer's like pathology and symptoms in an animal model. The effects of Apre and cilostazol, a reference drug, on the behavioral, biochemical, and pathological features of Alzheimer's disease induced by a high-fat/high-fructose diet combined with low-dose streptozotocin (HF/HFr/l-STZ) were investigated. Apre 5 mg/kg IP/day for 3 consecutive days per week for 8 weeks attenuated memory and learning deficits tested by novel object recognition, Morris water maze and passive avoidance tests. Apre treatment significantly decreased the number of degenerating cells, and abnormal suppression of gene expression of AMPA and NMDA receptor subunits in the cortex and hippocampus of the AD rat model compared to rats that received vehicle. A significant decrease in elevated levels of hippocampal amyloid beta, tau-positive cell count, cholinesterase activity, and hippocampal caspase-3, a biomarker of neurodegeneration, was also observed after treatment with Apre in AD rats compared to rats that received placebo. Furthermore, a significant decrease in pro-inflammatory cytokines, oxidative stress, insulin resistance and GSK-3 was demonstrated in AD aged rats treated by Apre. Our findings demonstrate that intermittent treatment with Apre can enhance cognitive function in HF/HFr/l-STZ rats which may be related to decreased pro-inflammatory cytokines, oxidative stress, insulin resistance and GSK-3β.