Statin therapy reduces the risk of AD: Clinic to bench translation for protective mechanism

Abstract

AbstractBackgroundCholesterol dysregulation is a well‐documented factor involved in the pathophysiology of Alzheimer’s Disease (AD). APOE4, which is involved in cholesterol transport, is recognized as the strongest genetic risk factor for late‐onset AD. In a previous study using clinical data, we showed that exposure to statins, a first‐line cholesterol lowering therapeutic, was associated with a reduced risk of developing AD. Another study showed the risk reduction associated with statins was greater in APOE4 carriers. Although the effects of statins in the periphery are well documented, the mechanisms by which statins act in the brain remain poorly understood.MethodThis study aimed to identify potential mechanisms by which statins impact AD pathology at a cellular level and the different response by APOE genotype. Humanized APP/APOE3 and APOE4 mouse neurons and astrocytes were co‐cultured and treated with vehicle or atorvastatin at clinically relevant concentrations. Metabolic flux analysis was used to determine the impact of statins on mitochondrial bioenergetics and dynamics. Multi‐electrode array (MEA) was used to conduct electrophysiological recordings on hippocampal neurons. Lipid droplet burden in astrocytic cells was determined using LipidTOX staining and confocal microscopy. qPCR and Western Blot were used to determine the expression of key proteins involved in cholesterol transport.ResultIn this study, hippocampal neurons treated with atorvastatin in the presence of astrocytic cells induced a significant increase in the number of spikes and spike frequency, as well as the number of bursts and number of spikes within a burst. In contrast, in the absence of astrocytes atorvastatin exposure in neurons did not exhibit a significant difference compared to vehicle. Electrophysiological properties were increased in a dose‐dependent manner and the effect was greater 24‐hours following treatment. Atorvastatin also increased astrocyte mitochondrial respiration whereas it did not in neurons or in neurons co‐cultured with astrocytes.ConclusionOutcomes of these analyses indicated that atorvastatin acts primarily on astrocytes. Specifically, atorvastatin increased mitochondrial respiration in astrocytes and increased synaptic activity on neurons which was astrocyte dependent. These results provide evidence of a neuroprotective role of atorvastatin by regulating lipid metabolism deficits in a cell‐specific manner.Acknowledgments: NIA P01AG026572 and R01AG057931 to RDB.