Statins Reduce Amyloid β-Peptide Production by Modulating Amyloid Precursor Protein Maturation and Phosphorylation Through a Cholesterol-Independent Mechanism in Cultured Neurons

Abstract

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been reported to attenuate amyloid-β peptide (Aβ) production in various cellular models. However, the mechanisms by which statins affect neuronal Aβ production have not yet been clarified. Here, we investigated this issue in rat primary cortical neurons using two statins, pitavastatin (PV) and atorvastatin (AV). Treatment of neurons with 0.2-2.5 μM PV or AV for 4 days induced a concentration- and time-dependent reduction in the secretion of both Aβ40 and Aβ42. Moreover, Western blot analyses of cell lysates showed that treatment with PV or AV significantly reduced expression levels of the mature form of amyloid precursor protein (APP) and Thr668-phosphorylated APP (P-APP), but not immature form of APP; the decreases in P-APP levels were more notable than those of mature APP levels. The statin treatment did not alter expression of BACE1 (β-site APP-cleaving enzyme 1) or γ-secretase complex proteins (presenilin 1, nicastrin, APH-1, and PEN-2). In neurons overexpressing APP via recombinant adenoviruses, PV or AV similarly reduced Aβ secretion and the levels of mature APP and P-APP. Statins also markedly reduced cellular cholesterol content in neurons in a concentration-dependent manner. Co-treatment with mevalonate reversed the statin-induced decreases in Aβ secretion and mature APP and P-APP levels, whereas co-treatment with cholesterol did not, despite recovery of cellular cholesterol levels. Finally, cell-surface biotinylation experiments revealed that both statins significantly reduced the levels of cell-surface P-APP without changing those of cell surface mature APP. These results suggest that statins reduce Aβ production by selectively modulating APP maturation and phosphorylation through a mechanism independent of cholesterol reduction in cultured neurons.

Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle

“…As a result, statin physiological effects have numerous and diverse mechanisms [40]. For example, protection against amyloid β-peptide production and Alzheimer’s disease was proposed to arise from modulating amyloid precursor protein maturation and phosphorylation in vitro [29]. Anti-metastatic activity of statins seems to arise from that activation of the AMPK-TOR signaling pathway and resulting statin-induced autophagy [66].…”

“…Beneficial effects of statin administration include major improvement in cardiovascular health [16], improved recurrence-free survival in breast cancer [44], protection against amyloid β-peptide production and Alzheimer’s disease [35,29]. On the other hand, unwanted consequences of statins such as new onsets of diabetes, myopathy, elevation of plasma cortisol levels have all been reported [5,46,54].…”

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

“…Statins are widely prescribed drugs for the treatment of hypercholesterolemia and act to reduce plasma cholesterol levels by inhibiting the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methy-lglutaryl-CoA reductase. In addition to the cholesterol lowering effect, statins have many pleiotropic effects, such as reducing Aβ production, suppressing inflammatory responses, protecting neurons from excitotoxins, apoptosis, and oxidative stresses, and promoting synaptogenesis [16][17][18][19] . In particular, statins have been linked to the reduced prevalence of AD in statin-prescribed populations [20,21] , the improved cognition in normo-cholesterolemic patients [22] , and the slowed cognitive decline in mild-to-moderate AD patients [23] .…”

Cyclic cis-Locked Phospho-Dipeptides Reduce Entry of AβPP into Amyloidogenic Processing Pathway

“…For example, treatment of rat primary cortical neurons with statins similarly decreases secreted Aβ40 and Aβ42, but significantly reduces matAβPP via a cholesterol-independent mechanism that involves selective reduction of AβPP phosphorylation at Thr668 [70], pointing to a central role of T668 phosphorylation in AβPP processing. In another example, treatment of HEK293 cells with the natural product 2,2′,4′-trihydroxychalcone (TDC) from Glycyrrhiza glabra (liquorice) root, reduced sAβPPβ without significant change in matAβPP (as we observe here), by serving as a non-competitive inhibitor of BACE1 catalytic activity [71].…”