Physiological or a-processing of amyloid-b precursor protein (APP) prevents the formation of Ab, which is deposited in the aging brain and may contribute to Alzheimer's disease. As such, drugs promoting this pathway could be useful for prevention of the disease. Along this line, we searched through a number of substances and unexpectedly found that a group of high-energy compounds (HECs), namely ATP, phosphocreatine, and acetyl coenzyme A, potently increased APP a-processing in cultured SH-SY5Y cells, whereas their cognate counterparts, i.e., ADP, creatine, or coenzyme A did not show the same effects. Other HECs such as GTP, CTP, phosphoenol pyruvate, and S-adenosylmethionine also promoted APP a-processing with varying potencies and the effects were abolished by energy inhibitors rotenone or NaN 3 . The overall efficacy of the HECs in the process ranged from three-to four-fold, which was significantly greater than that exhibited by other physiological stimulators such as glutamate and nicotine. This suggested that the HECs were perhaps the most efficient physiological stimulators for APP a-processing. Moreover, the HECs largely offset the inefficient APP a-processing in aged human fibroblasts or in cells impaired by rotenone or H 2 O 2 . Most importantly, some HECs markedly boosted the survival rate of SH-SY5Y cells in the death process induced by energy suppression or oxidative stress. These findings suggest a new, energy-dependent regulatory mechanism for the putative a-secretase and thus will help substantially in its identification. At the same time, the study raises the possibility that the HECs may be useful to energize and strengthen the aging brain cells to slow down the progression of Alzheimer's disease.

Elevated intracellular Ca2+ levels in the aging brain are widely thought to hyperactivate Ca2+ signaling and Ca2+-dependent enzymes, leading to neuronal death through an excitatory mechanism in Alzheimer's disease (AD). This "Ca2+ overload" hypothesis has been questioned by our theoretical analyses. To better understand the relationship between the "level" and functionality of Ca2+ in aging, in this study we simultaneously measured intracellular Ca2+ transients and calpain activity in cultured human fibroblasts. We found that Ca2+ transitions elicited by bradykinin were indeed overstayed or elevated in levels in old cells but, remarkably, calpain activity was decreased compared to young cells. Also, treating young cells with the energy inhibitor rotenone or with H2O2 recapitulated the Ca2+ overstay and calpain inactivation found in old cells. More importantly, treating old cells with high-energy compounds such as phosphoenol pyruvate or phosphocreatine, which boosted cellular ATP content, reduced the Ca2+ overstay and re-activated calpain. Moreover, Ca2+ levels and calpain activity were dramatically raised in the dying cells killed by detergent. Finally, Ca2+ oscillations induced by low dose of bradykinin in old cells exhibited lower spike frequency, but higher overall levels. Collectively, these results suggest that (a) Ca2+ overload in old cells arises from an inefficient Ca2+ handling system compromised by age-related energy depletion and oxidative stress; and (b) despite elevated levels, the functionality of Ca2+ signaling has diminished in old cells. Thus, the study reinforces the concept that tonic promotion of bioenergetics and Ca2+ signaling function is a reasonable and new paradigm to protect the aging brain cells to prevent AD.

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.

We have contended that senile conditions--illnesses after age 60 and fully age-penetrating, such as tooth, hearing or memory loss--are not distinct "diseases" in medical nature, because they are caused by aging. Since the pace of aging varies among individuals and is much influenced by risk factors, senile conditions will only affect some but not all elderly. However, perhaps due to its unusually heavy burdens and tremendous social pressures, senile dementia (SD) has been singled out from other senile conditions and redefined as a curable "disease" (Alzheimer's). This highly popular definition has thus opened a Pandora's box that has been confusing us up until now and warrants further scrutiny. In this article we discuss: a) what should we logically look for in SD beyond "pathogenic" factors?; b) why Ca2+, a central regulator in neurotransmission, should be the primary player in SD; c) why the functionality of Ca2+ signaling, or its vibrant wave frequency and amplitude, must undergo down-regulation during aging, though this is intriguingly accompanied by an increase of Ca2+ "levels"; d) why intervention for SD should target Ca2+ function by promoting energy metabolisms and by Ca2+ agonists such as caffeine and nicotine, but not by "antagonists" as widely believed; and e) why our study should focus on aging, not "cell death", a seemingly attractive paradigm but perhaps too late for intervention. We also seek answers for why unproven hypotheses can become dogmas and inhibit self-correcting mechanisms of science.

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