Castello MA, Soriano S.
Rational heterodoxy: Cholesterol reformation of the amyloid doctrine.
Ageing Res Rev. 2012 Jul 6;
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Whatever Aβ’s real role in AD might be, all human trials of therapeutic approaches targeting Aβ have so far failed. It’s time the scientific community moves on in searching and testing new mechanisms that more significantly contribute to the primary pathological steps of the disease. AD is a disease of aging; therefore, one should be looking at age-related mechanisms. Part of the problem is related to the lack of a true model for sporadic AD, and the other part to the definition of AD itself, which has locked researchers into narrowly studying some of its specific neuropathological features. The current transgenic models only represent, at best, partial disease or later stages in the full scope of sporadic AD. One needs to start looking at what happens upstream of the amyloid cascade of events.
This is precisely what Castello and Soriano have done in this very elegant hypothesis paper. The arguments are laid out rationally to set dysfunctional cholesterol dynamics as a primary event in AD. This review comes at a time of desperate need for new ideas and targets. Cholesterol and other lipids are not only fundamental, structural components of cells, but they (or their metabolites) also participate in signaling pathways of crucial relevance to aging, such as inflammation. Understanding these mechanisms will certainly provide a more significant insight into what might be the pathological driver(s) underlying AD.