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Calcium Regulation and the Aging Brain

Before studying Alzheimer’s specifically, science already found a connection between calcium and brain aging in general. Understanding calcium as a key factor in age-related brain dysfunction began to take shape in the 1980s, when a researcher named Zaven Khachaturian first suggested the importance of calcium regulation in the brain. His basic theory was that the brain’s ability to regulate intracellular calcium levels declined as a function of age. This decline resulted in small but persistent elevations in brain intracellular calcium levels. Chronic exposure to elevated intracellular calcium ultimately leads to neurotoxicity, which, he believed, was responsible for “normal” age related brain dysfunction. Since his original “calcium hypothesis” was proposed, several studies have supported Khachaturian’s theory.

In one study, researchers examined the time it took intracellular calcium levels to return to baseline after a stimulus. Specifically, they reported that it took neurons in the aged rat brain 25 seconds for calcium to return to homeostasis, as compared to 8 seconds for young rat neurons. 1 Additional studies have supported the concept of elevated intracellular calcium levels in the aging brain, reporting that after a stimulus, intracellular calcium levels are 30-85% higher in brain neurons of aged rats as compared to young rats. 2

Given that intracellular calcium levels are elevated in aged neurons, researchers were interested if there was a corresponding decrease in Ca2+ ATPase levels in the aging brain. To approximate human brains, researchers measured the amount of Ca2+ATPase in brain tissue of rats from age 5 months up to 34 months. (This would correspond to a normal age span of human beings from infancy to old age.) The study showed that Ca2+ATPase levels declined progressively with age. From age 5 months to 14 months Ca2+ATPase declined 16%, from age 14-22 months Ca2+ATPase declined an additional 15%, and from age 22-34 months. Ca2+ATPase declined an additional 16%. Looking at the big picture, Ca2+ATPase levels declined 47% over the lifetime of the rat. 3

 

Alzheimer’s and Disrupted Calcium

 

Homeostasis

 

Just as calcium plays a major role in the dysfunction of the normal aging brain, impaired calcium regulation is also thought to play an important role in the neurodegeneration found in Alzheimer patients. In addition to the normal age-related decline in Ca2+ATPase, in Alzheimer’s patients, calcium regulation is further impaired by the disease itself. 4,5

One hallmark of Alzheimer’s disease is the build-up of a sticky substance called amyloid beta-peptide senile plaques, which occur in the areas around nerve cells in the brain. Amyloid is a common form of protein in our bodies which normally causes no issues. For reasons that scientists have yet to pinpoint, Alzheimer’s disease causes the amyloid protein to divide improperly, creating the beta version, which is toxic to nerve cells in the brain. Amyloid beta-peptide has been shown to inhibit Ca2+ATPase in neurons.

In one study, brain tissue from four neurologically normal adults was exposed to amyloid beta-peptide, and there was an astonishing 35% reduction in Ca2+ATPase levels after one hour. 6

Additional studies provide corroborating evidence. Live imaging of neurons in mice that were made to mimic Alzheimer’s disease revealed elevated intracellular calcium levels near amyloid beta plaques, indicating that the net result of amyloid beta interaction with synapses is elevated intracellular calcium levels. Since synaptic transmission is tightly controlled by intracellular calcium levels, it may be that amyloid beta-peptide synaptic dysfunction is related to higher than normal intracellular calcium levels. 7

 

1 Verkhratsky A, Shmigol A, Kirischuk S, Pronchuk N, Kostyuk P. Age-Dependent Changes in Calcium Currents
and Calcium Homeostasis in Mammalian Neurons. Annuals New York Academy of Sciences 1994 Dec 15;
747:365-81.

2 Michaelis M, Foster C, Jayawickreme C. Regulation of calcium levels in brain tissue from adult and aged rats.
Mech Ageing Dev 1992 Mar 1;62(3):291-306.

3 Zaidi A, Gao J, Squier C, Michaelis L. Age-related decrease in brain synaptic membrane Ca2+ATPase in
F344/BNF1 rats. Neurobiology of Aging Vol 19, No 5, pp487-495.

4 Mata A, Impaiment of the activity of the plasma membrane Ca2+ATPase in Alzheimer’s disease. Biochem Soc
Trans 2011 June;39(3):819-22.

5 Berrocal M, Marcos D, Sepulveda M, Perez M, Avila J, Mata A. Altered Ca2+ dependence of synaptosomal
plasma membrane Ca2+ATPase in human brain affected by Alzheimer’s disease. FASEB J, 2009 Jun;23(6):1826-
34.

6 Mark R, Hensley K, Butterfield A, Mattson M. Amyloid Beta-Peptide Impairs Ion-Motive ATPase Activities:
Evidence for a Role in Loss of Neuronal Ca2+ Homeostasis and Cell Death. The Journal of Neuroscience,
September 1995, 15(9): 6239-6249.

7 Green K. Calcium in the initiation, progression and as an effector of Alzheimer’s disease pathology. Vol 13, Issue
9a Sept 2009 2787-2799.