Elsevier

Cell Calcium

Volume 34, Issues 4–5, October–November 2003, Pages 385-397
Cell Calcium

Neuronal and glial calcium signaling in Alzheimer’s disease

https://doi.org/10.1016/S0143-4160(03)00128-3Get rights and content

Abstract

Cognitive impairment and emotional disturbances in Alzheimer’s disease (AD) result from the degeneration of synapses and death of neurons in the limbic system and associated regions of the cerebral cortex. An alteration in the proteolytic processing of the amyloid precursor protein (APP) results in increased production and accumulation of amyloid β-peptide (Aβ) in the brain. Aβ has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and apoptosis by a mechanism involving disruption of cellular calcium homeostasis. By inducing membrane lipid peroxidation and generation of the aldehyde 4-hydroxynonenal, Aβ impairs the function of membrane ion-motive ATPases and glucose and glutamate transporters, and can enhance calcium influx through voltage-dependent and ligand-gated calcium channels. Reduced levels of a secreted form of APP which normally regulates synaptic plasticity and cell survival may also promote disruption of synaptic calcium homeostasis in AD. Some cases of inherited AD are caused by mutations in presenilins 1 and 2 which perturb endoplasmic reticulum (ER) calcium homeostasis such that greater amounts of calcium are released upon stimulation, possibly as the result of alterations in IP3 and ryanodine receptor channels, Ca2+-ATPases and the ER stress protein Herp. Abnormalities in calcium regulation in astrocytes, oligodendrocytes, and microglia have also been documented in studies of experimental models of AD, suggesting contributions of these alterations to neuronal dysfunction and cell death in AD. Collectively, the available data show that perturbed cellular calcium homeostasis plays a prominent role in the pathogenesis of AD, suggesting potential benefits of preventative and therapeutic strategies that stabilize cellular calcium homeostasis.

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

References (131)

  • M Kawahara et al.

    Molecular mechanism of neurodegeneration induced by Alzheimer’s beta-amyloid protein: channel formation and disruption of calcium homeostasis

    Brain Res. Bull.

    (2000)
  • B.L Kagan et al.

    The channel hypothesis of Alzheimer’s disease: current status

    Peptides

    (2002)
  • M.P Mattson et al.

    Abeta25-35 induces rapid lysis of red blood cells: contrast with Abeta1-42 and examination of underlying mechanisms

    Brain Res.

    (1997)
  • M.P Mattson et al.

    Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of beta-amyloid precursor protein

    Neuron

    (1993)
  • J Hardy

    Amyloid, the presenilins and Alzheimer’s disease

    Trends Neurosci.

    (1997)
  • Q Guo et al.

    Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-kB and stabilization of calcium homeostasis

    J. Biol. Chem.

    (1998)
  • S.L Chan et al.

    Presenilin-1 muations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons

    J. Biol. Chem.

    (2000)
  • A.S Yoo et al.

    Presenilin-mediated modulation of capacitative calcium entry

    Neuron

    (2000)
  • E Pack-Chung et al.

    Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor

    J. Biol. Chem.

    (2000)
  • C.L Lilliehook et al.

    Calsenilin enhances apoptosis by altering endoplasmic reticulum calcium signaling

    Mol. Cell. Neurosci.

    (2002)
  • G.W Glazner et al.

    Endoplasmic reticulum IP3-sensitive stores regulate NF-kB binding activity in a calcium-independent manner

    J. Biol. Chem.

    (2001)
  • S.T DeKosky et al.

    Structural correlates of cognition in dementia: quantification and assessment of synapse change

    Neurodegeneration

    (1996)
  • A Parent et al.

    Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1

    Neurobiol. Dis.

    (1999)
  • P.A Barrow et al.

    Functional phenotype in transgenic mice expressing mutant human presenilin-1

    Neurobiol. Dis.

    (2000)
  • H Hartmann et al.

    Apolipoprotein E and cholesterol affect neuronal calcium signalling: the possible relationship to beta-amyloid neurotoxicity

    Biochem. Biophys. Res. Commun.

    (1994)
  • L Meda et al.

    Glial activation in Alzheimer’s disease: the role of Abeta and its associated proteins

    Neurobiol. Aging

    (2001)
  • R.D Fields et al.

    ATP: an extracellular signaling molecule between neurons and glia

    Trends Neurosci.

    (2000)
  • J.T Neary

    Trophic actions of extracellular ATP: gene expression profiling by DNA array analysis

    J. Auton. Nerv. Syst.

    (2000)
  • F.E Murray et al.

    Elemental analysis of neurofibrillary tangles in Alzheimer’s disease using proton-induced X-ray analysis

    Ciba Found. Symp.

    (1992)
  • R.A Nixon et al.

    Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer’s disease

    Ann. N.Y. Acad. Sci.

    (1994)
  • A.C McKee et al.

    Hippocampal neurons predisposed to neurofibrillary tangle formation are enriched in type II calcium/calmodulin-dependent protein kinase

    J. Neuropathol. Exp. Neurol.

    (1990)
  • J Xiao et al.

    Alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer’s disease

    J. Neuropathol. Exp. Neurol.

    (1996)
  • M.L Miller et al.

    Transglutaminase cross-linking of the tau protein

    J. Neurochem.

    (1995)
  • B Stein-Behrens et al.

    Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus

    J. Neurosci.

    (1994)
  • T Harkany et al.

    Mechanisms of beta-amyloid neurotoxicity: perspectives of pharmacotherapy

    Rev. Neurosci.

    (2000)
  • M.P Mattson et al.

    Presenilin mutations and calcium signaling defects in the nervous and immune systems

    Bioessays

    (2001)
  • C O’Neill et al.

    Dysfunctional intracellular calcium homoeostasis: a central cause of neurodegeneration in Alzheimer’s disease

    Biochem. Soc. Symp.

    (2001)
  • R.L Rodnitzky

    Can calcium antagonists provide a neuroprotective effect in Parkinson’s disease?

    Drugs

    (1999)
  • W Paschen et al.

    Endoplasmic reticulum dysfunction—a common denominator for cell injury in acute and degenerative diseases of the brain?

    J. Neurochem.

    (2001)
  • E.P Simpson et al.

    Mechanisms of disease pathogenesis in amyotrophic lateral sclerosis. A central role for calcium

    Adv. Neurol.

    (2002)
  • M.P Mattson

    Cellular actions of beta-amyloid precursor protein, and its soluble and fibrillogenic peptide derivatives

    Physiol. Rev.

    (1997)
  • H.W Querfurth et al.

    Calcium ionophore increases amyloid beta peptide production by cultured cells

    Biochemistry

    (1994)
  • Q Guo et al.

    Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide

    Neuroreport

    (1996)
  • Q Guo et al.

    Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals

    J. Neurosci.

    (1997)
  • Q Guo et al.

    Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knockin mice

    Nat. Med.

    (1999)
  • M.P Mattson

    Apoptosis in neurodegenerative disorders

    Nat. Rev. Mol. Cell. Biol.

    (2000)
  • Q Guo et al.

    Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer’s disease

    Nat. Med.

    (1998)
  • C Culmsee et al.

    A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide

    J. Neurochem.

    (2001)
  • K Hensley et al.

    A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer’s disease

    Proc. Natl. Acad. Sci. U.S.A.

    (1994)
  • R.J Mark et al.

    Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death

    J. Neurosci.

    (1995)
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