Our "energy-Ca(2+) signaling deficits" hypothesis and its explanatory potential for key features of Alzheimer's disease.

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.

High-energy compounds mobilize intracellular Ca2+ and activate calpain in cultured cells: is calpain an energy-dependent protease?

Deficiency in energy metabolisms is perhaps the earliest modifiable defect in brain aging and sporadic Alzheimer's disease (sAD). Several high-energy compounds (HECs) such as ATP, phosphoenolpyruvate, phosphocreatine and acetyl coenzyme A have been shown to exhibit neuroprotective effects. To understand their mechanism of actions, we tested the effects of these HECs on intracellular Ca(2+), a central regulator in brain function.

Elevated [Ca2+]i levels occur with decreased calpain activity in aged fibroblasts and their reversal by energy-rich compounds: new paradigm for Alzheimer's disease prevention.

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.

High-energy compounds promote physiological processing of Alzheimer's amyloid-β precursor protein and boost cell survival in culture.

Physiological or α-processing of amyloid-β precursor protein (APP) prevents the formation of Aβ, 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 α-processing in cultured SH-SY5Y cells, whereas their cognate counterparts, i.

Evidence supporting the role of calpain in the α-processing of amyloid-β precursor protein.

Amyloid plaques are a hallmark of the aging and senile dementia brains, yet their mechanism of origins has remained elusive. A central issue is the regulatory mechanism and identity of α-secretase, a protease responsible for α-processing of amyloid-β precursor protein (APP). A remarkable feature of this enzyme is its high sensitivity to a wide range of cellular stimulators, many of which are agonists for Ca(2+) signaling.

What to look for beyond "pathogenic" factors in senile dementia? A functional deficiency of Ca²⁺ signaling.

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).