The state of intracellular Ca2+ in aging and in Alzheimer’s disease (AD) is a key but highly controversial issue and direct measurement of the Ca2+ fluctuations in the living human brain has not been possible thus far. We therefore further considered this issue from a theoretical perspective. Ca2+ signaling mediates many life processes including: fertilization, gene expression, cell division, growth and differentiation, muscle contraction, neurotransmission and memory formation.
It is common observation that these Ca2+-mediated activities in human life are highest in young adulthood but diminish during aging, indicating that Ca2+ signaling potency (or intracellular Ca2+ levels) must be decreased in aging and AD. A potential explanation for this phenomenon could be that the Ca2+-mediated processes are also energy-dependent processes, because they all utilize the free energy reserve of the body for “useful” work, and it is known that Ca2+ gradient formation and Ca2+ movement across cell membrane are driven by energy-dependent systems. This intimate relationship between energy and Ca2+ signaling implies that the potency of Ca2+ signaling would be affected by changes of energy levels, which would necessarily decline in aging. These may underlie the deficit of Ca2+ signaling in the presymptomatic stage of AD.
These considerations also support our view that Abeta and tau accumulation in AD is the result of inactivation of calcium-dependent enzymes, rather than overactivation of beta/(-secretases and some tau kinases. This is because most enzyme activities should be diminished, rather than overactivated, during aging. Furthermore, since energy/Ca2+ deficit is a natural event in aging, it follows that the accumulation of Abeta and tau would be initiated “spontaneously” as a result of “natural” aging, not necessarily by a “pathological” factor. Based on the analyses, we propose that intracellular Ca2+ deficit is most likely the primary and common cause (among the many contributing, secondary or individualized factors) for the plaque and tangle accumulation underlying sporadic AD. And we predict that this contention, though in contrast to many competing models, will be confirmed by the proposed experimentation in the future.
Source: Front Biosci 1999 Apr 1;4:A9-15
PMID: 10099137, UI: 99201494
(Neuroscience Research Laboratory, Medical Research Service (151), Bay Pines VA Medical Center, Bay Pines, Florida 33744, USA. email@example.com)