title: Our "energy-Ca(2+) signaling deficits" hypothesis and its explanatory potential for key features of Alzheimer's disease.
abstract: Sporadic Alzheimer's disease (sAD) has not been explained by any current theories, so new hypotheses are urgently needed. We proposed that "energy and Ca(2+) signaling deficits" are perhaps the earliest modifiable defects in brain aging underlying memory decline and tau deposits (by means of inactivating Ca(2+)-dependent protease calpain). Consistent with this hypothesis, we now notice that at least eight other known calpain substrates have also been reported to accumulate in aging and AD. Thus, protein accumulation or aggregation is not a "pathogenic" event, but occurs naturally and selectively to a peculiar family of proteins, and is best explained by calpain inactivation. Why are only calpain substrates accumulated and how can they stay for decades in the brain without being attacked by many other non-specific proteases there? We believe that these long-lasting puzzles can be explained by calpain's unique properties, especially its unusual specificity and exclusivity in substrate recognition, which can protect the substrates from other proteases' attacks after calpain inactivation. Interestingly, our model, in essence, may also explain tau phosphorylation and the formation of amyloid plaques. Our studies suggest that α-secretase is an energy-/Ca(2+)-dual dependent protease and is also the primary determinant for Aβ levels. Therefore, β- and γ-secretases can only play secondary roles and, by biological laws, they are unlikely to be "positively identified". This study thus raises serious questions for policymakers and researchers and these questions may help explain why sAD can remain an enigma today.
authors.affiliation: Aging Research Laboratory, Research and Development Service, Bay Pines Veterans Affairs Healthcare System Bay Pines, FL, USA ; Department of Molecular Pharmacology and Physiology, University of South Florida Tampa, FL, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Aging Research Laboratory, Research and Development Service, Bay Pines Veterans Affairs Healthcare System Bay Pines, FL, USA.
authors.forename: Huey T
authors.initials: HT
authors.lastname: Nguyen
keywords: Alzheimer’s disease; amyloid; calcium; energy; tau