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 Ca2+ signaling deficits” are perhaps the earliest modifiable defects in brain aging underlying memory decline and tau deposits (by means of inactivating Ca2+-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-/Ca2+-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.
Highlights
Sporadic Alzheimer’s disease has not been explained by any current theories, so new hypotheses are urgently needed.We proposed that “energy and Ca2+ signaling deficits” are perhaps the earliest modifiable defects in brain aging underlying memory decline and tau deposits
While much more studies are required for definitively resolving this issue, our findings suggest that higher static Ca2+ “levels” in aged cells result from energy depletion and lead to lower Ca2+ signaling potency
Which phosphatase among numerous in the brain should we focus on? This key question has long limited the progress of the study area with a standing dilemma: if any phosphatase is inactivated, the loss will be compensated by many other non-specific phosphatases, so how can tau stay phosphorylated for decades in the brain?
Summary
Alzheimer’s disease (sAD). (A) Proposes that energy deficiency is the earliest modifiable defect in brain aging, which causes, among other things, a Ca2+ signaling deficit underlying inefficient memory and the formation of plaques and tangles (by means of inactivating Ca2+-dependent proteases and phosphatases; not shown, see text below). (B) Explains why energy deficit decreases Ca2+ signal potency (by reducing Ca2+ wave frequency), and why this change can manifest as slow rising Ca2+ “levels” during aging and sharp Ca2+ rises in cell death. Www.frontiersin.org hypothesis is questionable because it: (i) derives from the flawed “disease” definition of sAD and rests on a presumptive “abnormal” pathway as its “cause”; (ii) defies the commonsense knowledge (e.g., how can the energy-dependent Ca2+ signaling be activated in the energy-depleted aging process?); and (iii) has not been supported by consistent clinical data after many trials, but is challenged by at least three studies reporting that calcium antagonists exhibit negative effects on cognition in the elderly (Heckbert et al, 1997; Maxwell et al, 1999; Wagner et al, 2012). While much more studies are required for definitively resolving this issue, our findings suggest that higher static Ca2+ “levels” in aged cells result from energy depletion and lead to lower Ca2+ signaling potency This intriguing phenomenon may happen because the frequency and amplitude of the Ca2+ waves in vivo may reduce by aging, but this change can manifest as a “Ca2+ overstay” or elevated steadystate “levels” in vitro (Figure 1B). The latter change, may not have any therapeutic values (Figures 1A,B)
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