Calcium and Health

With most major neurodegenerative diseases, there is an excess of unregulated calcium in the sensitive areas. As these diseases progress and the calcium imbalances grow more significant, the number of unregulated calcium ions in the nervous system increases. The body steadily loses its ability to control how calcium is stored and used. These unbound and excess calcium ions begin wreaking havoc on neurons. The unregulated calcium triggers excitotoxic events that will eventually kill the neurons. Currently, effective therapeutics that treat the problem of excess calcium ions are not available (Ripova et al., 2004 [1]).

Calcium-dependent processes have been shown to be important for associative learning in both adult and aged animals (Moyer et al., 1996 [2]; Thompson et al., 1996 [3]; Moyer et al., 2000 [4]). Also, compounds that block influx of calcium through L-type calcium channels have been shown to both improve associative learning in aged animals (Deyo et al., 1989 [5]; Disterhoft et al., 1993 [6]; Veng et al., 2003 [7]) and restore their electrophysiological properties to those commonly seen in young adults (Moyer et al., 1992 [8]; Moyer and Disterhoft, 1994 [9]; Thibault et al., 1998 [10]).

Pharmacological manipulation of calcium entry has been shown to be effective in increasing some aspects of cognitive function of the aged brain. Therefore, further exploration of Ca2+ homeostasis, regulation and signaling might reveal the mechanisms involved in the age-dependent decline in neuronal performance, and might aid the search for new therapeutic treatments. (Verkhratsky and Toescu, 1998 [11], Pascale and Etcheberrigaray, 1999 [12]).

The relationship between calcium, neuronal degeneration, calcium binding proteins, and aging suggest that a viable but as yet untapped treatment plan may involve replenishment of neuronal CaBPs, particularly in higher brain regions known to degenerate with advancing age, such as the hippocampus and associated medial temporal lobe (MTL) structures (Visser et al., 2002 [13]).

The Importance of Intracellular Calcium

Calcium is an essential second messenger that plays important roles in a plethora of neuronal functions, including synaptic plasticity, activation of kinases and phosphatases, regulation of gene expression, and excitotoxic cell death plasticity (Williams and Johnston, 1989 [14]; Bröcher et al., 1992 [15]; Uchitel et al., 1992 [16]; Choi, 1994 [17]; Yeckel et al., 1999 [18]). The latter is particularly important because, although calcium is vital to normal neuronal function, it is very tightly regulated and too much calcium is actually detrimental. Excessive calcium influx is particularly troublesome for aging neurons because they are less able to handle excessive calcium influx, at least partly due to decreases in calcium binding proteins, (CaBPs) which help to buffer intracellular calcium. A number of studies, suggest that when aged neurons are activated, they experience excessive calcium influx – particularly those neurons in brain regions vital for normal memory, such as the hippocampus and associated MTL structures (Moyer et al., 1992 [19] ; Moyer and Disterhoft, 1994 [20] ; Moyer and Brown, 1998 [21]; Moyer et al., 2000 [22]). With such a pivotal role in neuronal function, it is not surprising that calcium has been intensely studied in the fields of learning, memory, and aging.

Calcium Hypothesis of Aging

Over the last fifteen years, a unifying hypothesis has emerged which attempts to explain some of the cognitive deficits seen in aging. This hypothesis is referred to as the calcium hypothesis of aging (Khachaturian, 1987 [23]; Landfield, 1987 [24]; Khachaturian, 1994 [25]). It posits that dysregulation of calcium homeostasis is a primary factor contributing to aging-related learning and memory impairments observed in many species, including humans. Calcium-dependent processes have been shown to be important for associative learning in both adult and aged animals (Moyer et al., 1996 [26]; Thompson et al., 1996 [27]; Moyer et al., 2000 [28]). Also, compounds that block influx of calcium through L-type calcium channels have been shown to both improve associative learning in aged animals (Deyo et al., 1989 [29]; Disterhoft et al., 1993 [30]; Veng et al., 2003 [31]) and restore their electrophysiological properties to those commonly seen in young adults (Moyer et al., 1992 [32]; Moyer and Disterhoft, 1994 [33]; Thibault et al., 1998 [34]).