Neuronal and glial calcium signaling in Alzheimer’s disease
Introduction
There are currently more than 4 million Americans living with Alzheimer’s disease (AD), a devastating and always fatal neurodegenerative disorder characterized by progressive impairment of cognitive function and emotional disturbances. The disease process involves the degeneration of synapses and neurons in brain regions that play fundamental roles in learning and memory including the hippocampus, entorhinal cortex, basal forebrain, amygdala, frontal cortex, and inferior parietal cortex [1]. Two histological hallmarks of these brain regions of AD patients are the presence of aggregates of the amyloid β-peptide (Aβ) in the form of plaques, and the presence of filamentous intracellular aggregates of the microtubule-associated protein tau—the so-called neurofibrillary tangles.
Analyses of brain tissue from AD patients have provided evidence suggesting that alterations in cellular calcium homeostasis are associated with the neurodegenerative process. Levels of free and protein-bound calcium are increased in neurons containing neurofibrillary tangles as compared with tangle-free neurons [2]. Nixon and coworkers [3], [4] have shown that levels of activated calcium-dependent proteases are also increased in neurofibrillary tangle-bearing neurons. The increased levels of calcium may precede tangle formation because levels of calcium/calmodulin-dependent protein kinase II are increased in neurons that are vulnerable to degeneration [5] and is associated with paired helical filaments [6]. In addition, levels of tissue transglutaminase (a calcium-activated enzyme) are increased in AD brain tissue [7], and can induce cross-linking of tau protein in vitro [8]. Studies of cultured neurons have provided evidence that elevated intracellular calcium levels, resulting from overactivation of glutamate receptors, can induce changes in the cytoskeleton similar to those seen in neurofibrillary tangles [9]. Similar alterations in the cytoskeleton can be induced in hippocampal neurons in vivo in response to severe epileptic seizures; the alterations were exacerbated by physiological stressors that elevate glucocorticoid levels [10].
In the present article, we review data, primarily from this laboratory, that provide insight into the cellular and molecular mechanisms that result in perturbed neuronal calcium homeostasis in AD, and how altered calcium signaling plays a pivotal role in synaptic dysfunction and neuronal death. Due to space constraints we have not attempted a comprehensive review of this topic, but do acknowledge the many important contributions not cited here by way of reference to recent relevant review articles [11], [12], [13]. We also note at the outset that alterations in cellular calcium homeostasis occur in other neurodegenerative disorders including Parkinson’s and Huntington’s diseases, ischemic stroke, and amyotrophic lateral sclerosis [14], [15], [16], [17]. While the factor(s) that initiate the neurodegenerative cascade may differ among these disorders, oxidative stress and metabolic compromise are important contributors to perturbed neuronal calcium homeostasis in each disorder (Fig. 1). Dysregulation of calcium signaling, in turn, likely contributes to synaptic dysfunction and excitotoxic and/or apoptotic death of the vulnerable neuronal populations. Therefore, at least some of the cellular and molecular mechanisms described below in relation to AD, are also relevant to other neurodegenerative disorders, a fact easily appreciated by reading other articles in this special issue of Cell Calcium.
Section snippets
APP metabolites and neuronal calcium homeostasis
A major alteration in AD patients, and in some experimental models of AD, is altered proteolytic processing of the β-amyloid precursor protein (APP). The alteration involves increased cleavage at either end of Aβ by β- and γ-secretases resulting in increased production of Aβ, particularly the longer 42 amino acid Aβ which has a greater propencity to self-aggregate and is more toxic to neurons than the shorter 40 amino acid peptide [18]. In addition, cleavage of APP in the middle of the Aβ
Presenilins and neuronal calcium homeostasis
PS1 and presenilin 2 (PS2) are integral membrane proteins that are evolutionarily conserved and widely expressed in many different cells types; in the brain, neurons contain particularly high levels of PS1 and PS2. A role for PS1 and PS2 in the pathogenesis of AD was established when it was shown that mutations in PS1 or PS2 are responsible for some cases of early-onset autosomal dominant familial AD (FAD; [54]). PS1 mutations account for many more cases of FAD than do PS2 mutations, with more
Synapses are the primary sites of calcium dysregulation in AD
The following proteins involved in calcium regulation are highly concentrated in pre- and or post-synaptic terminals: voltage-dependent calcium channels (L, N, and T channels), ionotropic glutamate receptors (NMDA, AMPA, and kainate receptors), metabotropic glutamate receptors, ion-motive ATPases (Na+/K+-ATPase and Ca2+-ATPase), ER ryanodine and IP3 receptors, mitochondrial calcium-handling systems (calcium uniporter, ATP-sensitive potassium channels, permeability transition pore). Evidence
A note on apolipoprotein E
Apolipoproteins shuttle cholesterol from the blood into cells. Individuals with one or two copies of the E4 isoform of apolipoprotein E are at increased risk for atherosclerotic cardiovascular disease and AD, while those with one or both of the other two isoforms (E2 and E3) are at reduced risk [84]. Hartmann et al. [85] reported that ApoE amplifies calcium signaling in lymphocytes, and [86] showed that a peptide derived from the receptor binding domain of ApoE stimulates calcium influx and
Glial cell calcium homeostasis in Alzheimer’s disease
Neurons are not the only cell type in the brain that are affected in AD. Vulnerable brain regions exhibit activated microglial cells and astrocytes, which are often associated with amyloid deposits suggesting that the glial cells respond to Aβ [92]. Several effects of Aβ on cultured astrocytes and microglia have been reported. For example, Aβ and related lipid peroxidation impair glutamate transport [32], while sAPP enhances glutamate transport [93] in astrocytes. Aβ also induces the production
Conclusions and implications for disease prevention and treatment
The identification of mutations in APP and presenilins as the causal factors in some cases of early-onset inherited forms of AD allowed numerous studies in which the mutant genes have been shown to result in a disruption of cellular calcium homeostasis, with synapses being particularly vulnerable to such adverse effects of the mutations. The evidence for the involvement of perturbed cellular calcium homeostasis in AD pathogenesis has led to clinical trials of a few drugs known to stabilize
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