Mevastatin promotes neuronal survival against Aβ-induced neurotoxicity through AMPK activation

Abstract

Statins or HMG-CoA reductase inhibitors have been shown to be effective at lowering cholesterol levels, and the application of these molecules has gradually emerged as an attractive therapeutic strategy for neurodegenerative diseases. Epidemiological studies suggest that statin use is associated with a decreased incidence of Alzheimer's disease (AD). Thus, statins may play a beneficial role in reducing amyloid β (Aβ) toxicity, the most relevant pathological feature and pathogenesis of AD. However, the precise mechanisms involved in statin-inhibited Aβ toxicity remain unclear. In the present study, we report that mevastatin significantly protects against Aβ-induced neurotoxicity in SK-N-MC neuronal cells by restoring impaired insulin signaling. This protection appears to be associated with the activation of AMP-activated protein kinase (AMPK), which has long been known to increase insulin sensitivity. Our results also indicate that high levels of cholesterol likely underlie Aβ-induced neurotoxicity and that activation of AMPK by mevastatin alleviates insulin resistance. Signaling through the insulin receptor substrate-1/Akt pathway appears to lead to cell survival. These findings demonstrate that mevastatin plays a potential therapeutic role in targeting Aβ-mediated neurotoxicity. The molecule presents a novel therapeutic strategy for further studies in AD prevention and therapeutics.

Targeting AMPK by Statins: A Potential Therapeutic Approach

“…Kornelius et al, who evaluated the neuroprotective effects of mevastatin against Aβ deposition-induced neurotoxicity in SK-N-Mc human neuroblastoma cells, reported that this protection was associated with AMPK activation that may increase insulin sensitivity. They demonstrated that mevastatin reduced insulin resistance and Aβ deposition-induced neurotoxicity as a result of AMPK activation [ 67 ]. In another study, Singh et al examined the efficacy of lovastatin and 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, in experimental autoimmune encephalomyelitis in the murine model of multiple sclerosis, and showed that combination therapy provided more protection for mitochondria/peroxisome and myelin/axons than treatment with either alone.…”

Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease

“…In addition, statins have anti-inflammatory, antioxidant, and neuroprotective effects and are classified into two categories: hydrophilic (fluvastatin, mevastatin, and pravastatin) and lipophilic (simvastatin, lovastatin, atorvastatin) [ 209 ]. In vitro assays have shown that the use of these drugs decreases Aβ levels, and it has been proposed that they activate ADAM10 [ 210 ] and increase the activity of phospholipid transporters (PLTP), which results in the reduction of p-tau181 ( Table 1 ) [ 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 ].…”

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

“…Subsequently, Greco et al investigated the effect of AICAR on tau pathology and the downstream mechanism and they found that it reduces the formation of hyperphosphorylated tau by inhibiting GSK-3β [131]. Similarly, using different AMPK activators, Kim et al, Park et al, and Kornelius et al also showed that AMPK activation decreases tau hyperphosphorylation by inhibiting GSK-3β [38,127,133]. In these studies, the antitauopathy effect through GSK-3β inhibition was clearly implicated as the effects were reversed by compound C.…”