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The aging brain part 2: calcium homeostasis and a theory of brain aging.

Over 20 years ago, the calcium hypothesis of brain aging was first proposed. Multiple theories of aging exist, but brain aging is always associated with dysregulation of the calcium ion (Ca2+). Despite differences in etiology, the deregulation of calcium homeostasis consistently appears as the underlying mechanism of neuronal loss and dysfunction in growing old and in age-related diseases such as Alzheimer's, Parkinson's, ALS, and other dementias. (1) In part 1 of this review, brain aging was defined and the role of the Ca2+ in normal brain function reviewed. In part 2, the mechanisms for calcium-induced brain aging are reviewed.

Biological systems depend on the Ca2+ through the intrinsic chemistry of protein molecules. Neurons have a specialized network of proteins that mediate calcium activation of biochemical events. Research into brain aging has revealed that the cumulative demise of the network of calcium-mediated systems of brain biology can be blamed for "normal" aging process and many age-related dementias. In the brain, these systems are networked by proteins through the Ca2+ making calci urn dyshomeostasis the nexus of brain aging. (2), (3) The loss of calcium regulation that results in brain aging is fundamental to age-related brain diseases such as Alzheimer's and other poorly diagnosed dementias. (2) Memory loss, slower movement, sluggish reflexes, changes in perception, reduction in analytical tasks, diminished response time, poorer judgment, and personality changes can be documented in the aging process. These age-related changes are associated with changes in the health of the cells of the nervous system.

The Calcium Network of the Brain

Internal baseline concentrations of the Ca2+ are regulated by the cell through means of the energy-dependent plasma membrane Ca2+ pump (PmCA) and the sodium/ calcium exchanger (NCX). The NCX removes Ca2+ through an ATP dependent electrochemical gradient. The NCXs are distributed generally throughout the cell membrane and are activated by the rise in calcium concentrations. The PMCAs have a high binding affinity for calcium and are localized in synaptic regions, and this localization is involved in priming the presynaptic junction for neurotransmitter release. PMCAs are regulated by calmodulin, a calcium-activated protein with multiple targets, as well as other mechanisms giving stringent local control to the activation of the PMCA.

Other cell membrane channels, the glutamate-regulated channels, are responsible for the majority of neurotransmissions of the brain. The channels are found as ionotropic receptors or G-protein coupled receptors. Three forms of the ionotropic receptors exist: the kainite (KA), the AMPA, and the NMDA receptors. Of these, the NMDA receptors have a higher conductance and are permeable to sodium and calcium ions. Depolarization of the membrane by activated KA/AMPA receptors stimulates activation of the NMDA receptors also by glutamate; the combination of controls for activation allows high increases in the calcium into the cell. This triggers key secondary messaging for various signal pathways. This localized control over NMDA receptor activation determines long-term potentiation and synaptic plasticity associated with learning and memory. (4)

The extensive endoplasmic reticulum (ER) found distributed throughout neurons store Ca2 + through a spectrum of channels, buffers, and sensors that are integrated for Ca2 + homeostasis. Ca2 +s are released primarily through the ryanodine (RyR) and inositol 3-phosphate (InsP3) receptors. Each has three different subsets of receptors with different sensitivity to activation by the calcium ion. They are distributed both spatially and temporarily throughout the ER of cells and differentially in the brain tissues that reflect specialization of regions in the brain. The release of Ca2+ by these calcium-activated receptors produces a wave of polarization across the ER. The organization of receptor placement creates different wave properties that are relevant to the formation of neuronal plasticity. Uptake of Ca2+ is by energy-dependent ER calcium ATPase pumps or SERCA, a family of pumps expressed in patterns relevant to the needs of the cell and brain region. The ER also contains calcium-binding buffering proteins, calreticulin and calsequestrin and others having low affinity for the calcium ion, adding to the fine control over calcium concentrations.

Mitochondria are organelles specialized to carry out the respiration of sugars and production of chemical energy for the cell. They are also an important Ca2+ buffer, sequestering the ion through a uniporter that creates an electrochemical potential to pull the ion into the cell. The enzymes of respiration are calcium regulated so that conductance of Ca2+ occurs when the concentration is high and ATP/ADP ration is low. The Ca2+ is exported from the mitochondria through a NCX or through a proton exchanger. Other means of calcium export involve the formation of a transient pore in the mitochondrial membrane, an event that appears to occur in pathological conditions of cell physiology.

A large family of calcium-binding proteins serve as sensors and buffers of the calcium ion. The sensing protein calmodulin is a calcium-activated protein that renders graded changes in the concentration of the calcium ion into graded responses through activation of various enzymatic pathways, including local changes in membrane proteins to modulation of genetic expression. Other calcium-activated sensor proteins switch compartmentalization of signal cascades or modify proteolytic processing of other proteins and regulate signal transduction systems.

Calcium-binding proteins have a few types of calcium-binding domains with each having a large repertoire of permutations with which to bind calcium. (5) Some permutations of the calcium-binding domain bind the ion strongly and others weakly. Certain proteins bind calcium with large conformational changes in their structure, and other calcium-binding associations cause subtle changes. (6) Proteins that bind the ion strongly with minor changes in conformation are buffers against calcium toxicity. Proteins that bind weakly and reversibly may undergo very large changes in conformation. These changes activate the protein to catalyze enzymatic reactions or to signal gene expression. The calcium-protein association permits cellular activity to proceed in a finely tuned orchestration of biochemical regulation that makes life possible. The signature motif for calcium-binding domains is the EF-hand structure. It has been found in over 1000 unique proteins in the animal kingdom, and several hundred proteins have been found in the human genome. (7), (8) The brain cell has been engineered with extreme prejudice to perform small miracles from microsecond to microsecond, using calcium to orchestrate the power of control.

Other proteins such as calretinin, calbindin, and parvalbumin function as localized calcium buffers, especially in the pre- and postsynaptic regions, regulating Ca2+ densities to affect the sensitivity of the neuron to various stresses such as oxidative damage, ischemia, and depolarization. Furthermore, the expression and distribution of these proteins in critical locations of the neuron, including the internal membranes of the cell, contribute to a number of neuronal subtypes in tissues specialized for information flow and storage within the brain.

Neuronal Excitability and Synaptic Plasticity Affected

In essence, changes in synaptic plasticity and neuronal excitability result in cognitive decline typical of normal aging. The collective demise of calcium regulating systems of the neuron establishes a chronic elevation of intracellular Ca2 + concentration. This affects synaptic transmission. Long-term potentiation (LTP) increases synaptic activity, while long-term depression (LTD) reduces it. LTP strengthens the synapse, while LTD weakens synaptic connections. Both determine synaptic plasticity by high- or low-frequency stimulation, respectively. The imbalance of Ca2+ interferes with the sensitivity of these two forms of signal; the threshold for LTP is increased and the threshold for LTD is decreased. The overall effect is to reduce synaptic connectivity; LTP signals are down, LTD signals increase. Memories are being lost and new experiences difficult to record; learning and memory are impaired.

Age-Related Changes in Brain Cell Biology

Aged neurons show higher basal internal Ca2 + concentrations than younger neurons, and each of the calcium-dependent systems has shown abnormalities that contribute to calcium toxicity. The age-dependent changes in voltage-operated Ca2+ channels (VOCC) of the cell membrane, which regulate calcium entry upon neuronal depolarization, include two phenomena that lead to excess calcium entering the neuron. Some types of VOCC increase in their excitability, having lower thresholds to calcium entry. (9) Other calcium channels increase in number in aged neurons, increasing the entry points for Ca2+ upon activation. (10) Why the cell responds to age by increasing the presence of some channels when other channels are hypersensitive is unknown, but the result is excessive calcium entry into older brain cells with changes in depolarization and repolarization events (afterhyperpolarization). (10)

The NMDA receptors localized at the synapse activate upon the release of the neurotransmitter glutamate. The current thinking is that there is an age-related decline in the number of these receptors, but no change in glutamate affinity. (11) Different RNA editing has also been detected in a developmentally regulated way for the receptor protein in aged cells, resulting in electrophysiological changes in channel responsiveness and an increase in the peak current required for activation and its association with Ca2+ toxicity. (3) This would effectively reduce the neurotransmission signals while simultaneously increasing the electrical current demand for activation resulting in excess calcium entry to activate the channel, both of which establish adverse signaling, contributing to alteration in synaptic communications. In addition, gene-to-gene interactions of the NMDA receptor gene are magnified in age-related memory studies on carriers of certain genotypes. (12) This suggests that genetics plays a role in healthy aging when brain resources are at a premium.

Studies of the nerve endings of the cerebrocortex show that the activity of calcium extrusion by the NCX is reduced in the aged brain. (13), (14) The transporter has a reduced affinity for the Ca2+. (15) In addition, the calcium-activated protease calpain inactivates certain but not all forms of the NCX of the neuron, contributing to the failure to maintain baseline Ca2 + concentrations. (16) Chronic increases in basal Ca2 + levels raise this aberrant protease activity, adding to Ca2+ dyshorneostasis.

Furthermore, impairments in the calcium sequestration and extrusion pumps of either the ER (SERCA pumps) or the plasma membrane energy-dependent calcium pumps (PMCA) have reduced activity in aged neurons. This raises the levels of intracellular calcium, resulting in a chronic overload of Ca2 + in the cytoplasm of neurons, reducing neuronal excitability and the dynamics of neuronal plasticity of aged cells. (17) Proteins that compose the calcium network undergo oxidative modification through time, resulting in conformational changes, aggregation, and internalization from the plasma membrane and proteolytic degradation by the calcium-activated calpains and caspases. (17) Additionally, genetic deterioration and reduced protein turnover in the cell add to the accumulation of defective proteins. (18)

Afterhyperpolarization events are calci urn-dependent processes that increase in duration and decrease neuronal excitability in aged brain cells. (19) This is known to lead to difficulty in processing and storing new information, making learning difficult. (19), (20) Increased afterhyperpolarization also increases the residence time of high calcium concentrations, adding to the chronic activation of calcium-sensitive messaging systems and inducing mitochondria into oxidative stress with concomitant damage to the mitochondria and the ce11. (20)

In aging brain cells, the mitochondria show extensive oxidative damage to the internal membrane structures responsible for housing the proteins of the respiratory chain. (21), (22) Chronic exposure of mitochondria to calci urn overload leads to dysfunction and disruption of the organelle and programmed cell death of brain cells. (21), (23) Damage to DNA, the internal lipid membrane, and to proteins occurs, reducing the efficiency of energy production and the availability of chemical energy to energize the calcium pumps of the ce11. (24) Genetic damage by oxidative stress mutates proteins, destroying their antioxidative function and sensitizing the organelle to calcium overloads, toxic mechanisms, and dysfunction. (25) A cycle of chronic excessive Ca2+ in the cell is maintained. Over the years, this mitochondrial damage contributes to neurodegeneration and programmed cell death by the mitochondrial pathway. (24-26)

Calcium-binding proteins that function to buffer the Ca2+ are reduced in aged brain cells. (27), (28) Calcium buffers modulate the short-lived burst of transient calcium increases in a manner that shapes and enhances the precise cellular impact of the Ca2+ on neuronal activity. (29), (30) These proteins regulate the amplitude and duration of the transient calcium signal, fine-tuning the cell's response to the calcium signal and determining the extent of such processes as neuronal plasticity. (29), (31) The short- and long-term potentiation of neuronal signals determines the extent of synaptic modulations that result in either short- or long-term memories.

Extensive studies on calcium buffering proteins in regions of the brain known to be vulnerable to age-related diseases such as Alzheimer's have shown huge losses of these proteins in such regions as the hippocampus, where memory is integrated, and the basal forebrain, where learning is regulated. (20), (31-36) The reduction in calcium-buffering proteins appears to be due to a reduced level of gene expression as well as severe oxidative damage. (36), (37) The damage to these proteins is from aggregation and an age-related decline in cellular repair and protein turnover mechanisms. (37), (38) This loss of buffering capacity increases the oxidative load on the cell, resulting in corresponding increases in the concentrations of oxidized proteins. (38) Neuronal plasticity is weakened by the reduction in the fine-tuning of Ca2+ concentrations afforded by buffering proteins. These important changes are correlated to age-related deterioration in learning, memory recall, and other measurements of cognitive function.

Collectively, the multiple defects in calcium homeostasis from the increased release of calcium from the ER, reduction in calcium extrusion through the cell membrane, the reduction in buffering capacity, and the impairment of calcium pumps, also the impairment of the mitochondrial sinks, result in changes to neuron function and cell viability. (39) Neurons become hypersensitive to innervation but sluggish in recovery. Synaptic response is reduced as well, interfering with synaptic communication and diminishing neuronal plasticity. (39) Learning andl memory become impaired, and the demise of the calcium network of neuronal regulation imparts the sluggish response and behavior to the elderly. Cells may undergo a silencing of synaptic pathways (LTD) that weakens memory networks. (40), (41) Furthermore, the compromise in the orchestration of the fine-tuning of the calcium-protein networks of the brain enhances vulnerability to damage and to disease conditions, leading to dementias such as Alzheimer's. (30)

With these considerations, the final section of this review (part 3) will examine preventative and potential therapeutic opportunities for intervening in the demise of cognition as an age-related phenomenon.

Notes

(1.) Nikoletopoulou V, Tavernarakis N. Calcium homeostasis in aging neurons. Front Gene. 2012;3:200.

(2.) Thibault 0 et al. Hippocampal calcium dysregulation at the nexus of diabetes and brain aging. Fur Pharmacol. 2013;719(1-31:34-43.

(3.) Toescu CE. Altered calcium homeostasis in old neurons. Chapter 14 in: Riddle DR, ed. Brain Aging: Models, Methods, and Mechanisms. Boca Raton, FL: CRC Press; 2007.

(4.) Asztely F, Gustafsson B. lonotropic glutamate receptors: Their role in the expression of hippocampal synaptic plasticity. Mol Neurobiol. 1996;12:1-11.

(5.) Lewit-Bentley Al, Rety S. EF-hand calcium-binding proteins. Curr Opin Struct Biol. 2000;10:637-643.

(6.) Forsen S, Kordel J. Calcium in biological systems. In: Bertini I. Bioinorganic Chemistry. Mill Valley, CA: Science Books; 1994:107-166.

(7.) Henikoff S. ENCODE and our very busy genome. Nat Genet. 2007;39(7):17-18.

(8.) Chazin WI. Relating form and function of EF-hand calcium binding proteins. Acc Chem Res. 2011;44(3): 171-179.

(9.) Murchison D, Griffith WH. High-voltage-activated calcium currents in basal forebrain neurons during aging. 1 NeuroPhysiol. 1996:76:158.

(10.) Murchison D, Griffith WH. Low-voltage activated calcium currents increase in basal forebrain neurons from aged rats. 1 Neurophysiol. 1995;74:876.

(11.) Magnusson K. The aging of the NMDA receptor complex. From Biosci. 1998;3:e70-e80.

(12.) Papenberg GI , Li SC, Nagel 1E, et al. Dopamine and glutamate receptor genes interactively influence episodic memory in old age. Neurobiol Aging. 2014;35(5):1213.e3-8.

(13.) Michaelis ML. Ca2 + handling systems and neuronal aging. Ann N Y Acad Sci. 1989;568:89-94.

(14.) Canzoniero LM. The Na + -Ca2 + exchanger activity in cerebrocortical nerve endings is reduced in old compared to young and mature rats when it operates as a Ca2 + influx or efflux pathway. Biochim Biophys Acta. 1992;1107:175-178.

(15.) Michaelis ML, Johe K, Kilos TE. Age-dependent alterations in synaptic membrane systems for Ca2 + regulation. Mech Ageing Dev. 1984;25:215-225.

(16.) Atherton J, Kurbatskaya K, Bondulich M, et al. Calpain cleavage and inactivation of the sodium calcium exchanger-3 occur downstream of A13 in Alzheimer's disease. Aging Cell. 2014;13(1):49-59.

(17.) Zaidi A. Plasma membrane Ca-ATPases: Targets of oxidative stress in brain aging and neurodegeneration. World 1 Biol Chem. 2010;1(9):271-280.

(18.) Saez I, Vilchez D. The mechanistic links between proteasome activity, aging and age-related diseases. Curr Genomics. 2014;15(1):38-51.

(19.) Matthews EA, Linardakis JM, Disterhoft JF. The fast and slow afterhyperpolarizations are differentially modulated in hippocampal neurons by aging and learning.] Neurosci. 2009;29(15):4750-4755.

(20.) Matthews EA, Schoch S. Dietrich D. Tuning local calcium availability: cell-type-specific immobile calcium buffer capacity in hippocampal neurons. 1 Neurosci. 2013;33(36):14431-14445.

(21.) Yi M et al. Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. Cell Biol. 2004;167(4):661-672.

(22.) Barsukova AG, Bourdette D, Forte M. Mitochondrial calcium and its regulation in neurodegeneration induced by oxidative stress. Eur I Neurosci. 2011;34(3):437-447.

(23.) Marques-Aleixo I, Rocha-Rodrigues S, Santos-Alves E, et al. In vitro salicylate does not further impair aging-induced brain mitochondrial dysfunction. Toxicology. 2012;302(1):51-59.

(24.) Kazachkova N, Ramos A, Santos C, Lima M. Mitochondrial DNA damage patterns and aging: revising the evidences for humans and mice. Chang Gung Med 1. 2009;32(2):113-132.

(25.) Kawamata H1, Manfredi G. Mitochondrial dysfunction and intracellular calcium dysregulation in ALS. Mech Ageing Dev. 2010;131(7-8):517-526.

(26.) Martin L. Biology of mitochondria in neurodegenerative diseases. Prog Mol Blot Transl Sci. 2012;107:355-415.

(27.) Potier B, Jouvenceau A, Epelbaurn I, Dutar P. Age-related alterations of GABAergic input to CA1 pyramidal neurons and its control by nicotinic acetylcholine receptors in rat hippocampus. Neuroscience. 2006;42(1):187-201.

(28.) Ouda L, Burianova J, SyIca J. Age-related changes in calbinclin and calretinin immunoreactivity in the central auditory system of the rat. Exp Ceronu.d. 2012;47(7):497-506.

(29.) SchwaIler B. Cytosolic Ca2 + buffers. Cold Spring Harb Perspect Biol. 2010;2(11):a004051.

(30.) Palop JJ, Jones B, Kekonius L, et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Nat! Acad Sci USA. 2003;100(16):9572-9577.

(31.) Moyer JR Jr, Furtak SC, McGann IP, Brown TH. Aging-related changes in calcium-binding proteins in rat perirhinal cortex. Neurobiol Aging. 2011;32(9):1693-1706.

(32.) Geula C, Bu J, Nagykery N, et al. Loss of calbinclin-D28k from aging human cholinergic basal forebrain: relation to neuronal loss. I Comp Neurol. 2003;455(2):249-259,

(33.) Bu J, Sathyendra V, Nagykery N, Geula C. Age-related changes in calbindin-D28k, calretinin, and parvalbumin-immunoreactive neurons in the human cerebral cortex. Exp Neurol. 2003;182(1):220-231.

(34.) Mufson EL Ginsberg SD, lkonomovic MD, DeKosky ST. Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. I Chem Neuroanat. 2003;26(4):233-242.

(35.) Armbrecht HJ, Boltz MA, Kumar VB, Flood JF, Morley JE. Effect of age on calcium-dependent proteins in hippocampus of senescence-accelerated mice. Brain Res. 1999;842(2):287-293.

(36.) Kishimoto Jo Tsuchiya T, Cox Ho Emson PC, Nakayama Y. Age-related changes of calbindin-D28k, calretinin, and parvalbumin mRNAs in the hamster brain. Neurobiol Aging. 1998;19(1):77-82.

(37.) Robison AJ, Winder DG, Colbran RI, Bartlett RK. Oxidation of calmodulin alters activation and regulation of CaMKII. Biochem Biophys Res Commun. 2007;356(1):97-101.

(38.) Squier T. Oxidative stress and protein aggregation during biological aging. Exp Gerontol. 2001;36(9):1539-1550.

(39.) Nikoletopoulou and Tavernarakis. Op cit.

(40.) Nicholls RE, Alarcon JM, Malleret G, et al. Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility. Neuron. 2008;58 (1):104-117.

(41.) Malleret G, Alarcon INA, Martel G, et al. Bidirectional regulation of hippocampal long-term synaptic plasticity and its influence on opposing forms of memory. I Neurosci. 2010;30(10):381.

Dr. Moran is the director of manufacturing science for Quincy Bioscience and has over 25 years of practical recombinant fermentation experience. He is responsible for the development of practical and efficient manufacturing techniques for apoaequorin and also for accomplishing scaleup capabilities to include continuous batch manufacturing. Dr. Moran holds a PhD in genetic engineering and a master's degree in microbiology from Ohio University.
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Title Annotation:Aging Brain
Author:Moran, Dan
Publication:Townsend Letter
Article Type:Report
Date:Nov 1, 2014
Words:3374
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