Diverse effects of statins in Alzheimer’s disease

Statins are a widely prescribed class of drugs that inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis. In addition to promoting cardiovascular health by preventing atherosclerosis, an independent benefit of statins has been hypothesized for brain health. Both observational and experimental data support a role for cholesterol trafficking and metabolism in Alzheimer's disease (AD) and suggest that statins may be protective. Modulating brain cholesterol can alter intramembrane proteolysis in lipid rafts, especially the activity or turnover of secretase enzymes involved in the generation of β-amyloid peptide (Aβ). Indeed, statins have been reported to potentiate the beneficial α-secretase processing of amyloid precursor protein and to decrease Aβ in cerebrospinal fluid. In addition, statins have been implicated in various anti-inflammatory and antiapoptotic pathways. Yet, despite early enthusiasm for statins as cognitive-enhancing drugs, randomized clinical trials have not shown a benefit for statins in changing the course of AD. Recent work by Yamamoto et al. now adds to our understanding of the complex effects of statins in the brain by demonstrating that statins induce proteolytic pathways that are involved in the degradation of Aβ. Using a rat astrocyte model, they report that statin treatment paradoxically decreased the metalloproteinase neprilysin (NEP) in the membrane fraction, although leading to a significant increase in soluble NEP in the extracellular space. Moreover, by pharmacologically blocking MAP kinase pathways or adding exogenous mevalonate, they were able to discriminate between the cholesterol-lowering and intracellular-signaling effects of statins. The authors concluded that statins are capable of potentiating Aβ degradation via astrocytes as well as neurons, independent of cholesterol trafficking. As the primary enzyme responsible for Aβ degradation in the brain, NEP expression is inversely correlated with AD pathology in humans and in animal models. Interestingly, NEP is up-regulated in mild cognitive impairment, perhaps as a counterregulatory mechanism that ultimately becomes overwhelmed and fails. Although mainly found in presynaptic terminals of neurons, NEP expression has been previously reported in activated astrocytes and microglia. Focusing exclusively on glia, Yamamoto et al. show that statins induced functional and morphological changes in astrocytes that are linked to MAP kinase pathways causing extracellular NEP release. The choice of the statin simvastatin in this study was important because it is more lipophilic and penetrates the blood-brain barrier to a greater extent than other statins. Some have proposed that the lack of treatment effect of statins on dementia in prior clinical trials was due to statin formulations that did not efficiently cross the blood-brain barrier, as well as delayed treatment and reliance on insensitive clinical scales. In terms of the translational potential, it is important to remember that—particularly in complex multigene diseases like AD—"druggable" targets such as kinases may have off-target effects that result in no net benefit. Also, statins are known to have a range of mechanistic effects in distinct cell types, which need to be directly compared in coculture models. In summary, Yamamoto et al. propose an important functional link between activated glia and regulated proteolysis of Aβ in extracellular fluid, mediated through a MAP kinase pathway. Whether or not modulators of MAP kinase signaling in astrocytes will be effective in lowering global brain concentrations of Aβ, drugs that target release of Aβ after proteolysis or modulate cholesterol are worth exploring further. N. Yamamoto et al., Simvastatin and atorvastatin facilitates amyloid β-protein degradation in extracellular spaces by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways. Glia 10.1002/glia.22974 (2016). [[Abtract]][1] [1]: http://onlinelibrary.wiley.com/doi/10.1002/glia.22974/abstract