Elsevier

Cell Calcium

Volume 38, Issues 3–4, September–October 2005, Pages 427-437
Cell Calcium

Calcium dysregulation in Alzheimer's disease: Recent advances gained from genetically modified animals

https://doi.org/10.1016/j.ceca.2005.06.021Get rights and content

Abstract

Alzheimer's disease is a progressive and irreversible neurodegenerative disorder that leads to cognitive, memory and behavioural impairments. Two decades of research have implicated disturbances of intracellular calcium homeostasis as playing a proximal pathological role in the neurodegeneration associated with Alzheimer's disease. A large preponderance of evidence has been gained from the use of a diverse range of cell lines. Whilst useful in understanding the principal mechanism of neurotoxicity associated with Alzheimer's disease, technical differences, such as cell type or even the form of amyloid-beta used often underlie conflicting results. In this review, we discuss recent contributions that transgenic technology has brought to this field. For example, the triple transgenic mouse model of Alzheimer's disease has implicated intraneuronal accumulation of the amyloid-beta peptide as an initiating factor in synaptic dysfunction and behavioural deficits. Importantly, this synaptic dysfunction occurs prior to cell loss or extracellular amyloid plaque accumulation. The cause of synaptic dysfunction is unknown but it is likely that amyloid-beta and its ability to disrupt intracellular calcium homeostasis plays a key role in this process.

Introduction

Alzheimer's disease (AD) is the most common form of age-related dementia in the elderly. Unfortunately, as the average age of our population continues to increase, there is also a concomitant rise in the number of people afflicted with this debilitating disorder. Currently, it is estimated that one in 10 persons over 65, and more than a third of all people over 80 have AD. According to United Nations population projections, it is estimated that 370 million people will be older than 80 years by 2050 [1]. The aging of the world's population, therefore, will potentially pose an immense social and economic burden on future societies as this susceptible cohort continues to rapidly expand. Thus, a better understanding of the molecular events underlying AD will no doubt prove invaluable for combating this affliction.

Alois Alzheimer first described the pathological hallmarks of this disorder in 1906, observing strange alterations of the neurofibrils and foci, which were built up by a “peculiar substance” [2]. Our understanding of the molecular signatures of these hallmark lesions have been refined since his initial description. We now appreciate that neuritic and diffuse senile plaques are composed primarily of a small peptide called β-amyloid (Aβ), whereas the intracellular neurofibrillary tangles are composed of aggregates of hyperphosphorylated tau protein. The neuritic (or senile) plaques are dense deposits of Aβ around which dystrophic neuronal cell processes are observed. Plaques are generally noted within various parts of the brain but are especially abundant within the cerebral cortex, hippocampus and amygdala [3]. It is the gradual build-up of Aβ that is generally believed to account for the onset of this form of dementia [4]. Strong support for this hypothesis comes from human genetic data although recent advances in transgenic models have also provided critical corroborating evidence [5], [6], [7]. The preponderance of evidence supports a role for Aβ as the initial trigger of this disease in a process known as the amyloid cascade hypothesis. However, even though Aβ may trigger all forms of this disease, it should not preclude investigating and understanding other molecular and cellular aspects of AD even if they lie downstream of Aβ. In this regard calcium dysregulation, for example, represents a critical molecular defect that potentially can be attenuated with appropriate therapies. Moreover, it is interesting to note that Aβ and tau can both be influenced by calcium dysregulation, and alternatively the accumulation of these lesions can perturb calcium regulation. The point of this article is not to exhaustively review the entire body of literature concerned with calcium and AD but to focus on recent data generated using in vivo models. Here, we discuss advances in understanding the role of calcium dysregulation in AD with particular emphasis on the contribution of genetically modified animals. For a more comprehensive review we refer the reader to a recent review [8].

Section snippets

APP processing

Before we describe the evidence for calcium dysregulation in AD, it is critical to understand the process by which Aβ is generated and the influence that mutations have on the processing of amyloid precursor protein (APP). Aβ is generated by the sequential cleavage of APP, a type I integral membrane protein anchored to the plasma membrane and internal membranes of the ER, Golgi and trans-Golgi apparatus. Aβ is generated in very small quantities in normal healthy individuals and does not

Genetics and AD

Most cases of AD are not caused by a specific genetic defect but are sporadic in nature and are typically characterized by a later age of onset. However, there are a significant number of cases that are inherited in an autosomal dominant manner, and generally these forms manifest at an earlier age of onset. Several such mutations occur within the APP gene and cluster around the various secretase sites [1] Surprisingly, APP mutations account for a small percentage of FAD cases. Mutations in the

Calcium homeostasis and knowledge gained from in vivo studies

In addition to direct effects on Aβ formation, presenilin mutations have profound effects on cellular calcium homeostasis [26]. This feature of presenilins has received a great deal of attention over the past 10 years because of its potential role in contributing to the neurodegenerative phenotype. Along these lines, it is notable that every clinical mutation investigated appears to disrupt calcium signalling (Table 1).

Initial observations regarding the role of the presenilins in calcium

Calcium dysregulation as a mechanism underlying Aβ-mediated toxicity

The precise mechanism through which Aβ exerts its influence on LTP and hence learning and memory is still not understood but is proposed to involve disruption of intracellular calcium homeostasis [50]. Indeed, the role for alterations of intracellular calcium dynamics in modulating LTP was first reported by Bliss and Lomo who showed that intracellular injection of the calcium chelator EGTA reversed the enhancement of LTP reported in hippocampal neurons [51]. More recent evidence has indicated a

Voltage-gated calcium channels

It has previously been shown that exogenously applied Aβ can be neurotoxic, yet this effect is abrogated when cell cultures are incubated in calcium-free solutions [58], [62]. These findings suggest that extracellular calcium plays a key role in Aβ-mediated cell death. Furthermore, Brorson and colleagues have demonstrated that micromolar concentrations of Aβ fragments induce a rapid increase in intracellular calcium levels that can be attenuated by the addition of L-type VGCC antagonists [63].

Aβ and its role in forming a novel calcium-conducting channel

In addition to modulating the activity of existing calcium channels, studies indicate that Aβ can also form novel channels. The first such report described the formation of rudimentary Aβ ion channels in lipid bilayers, alongside similar hydrophobic peptides such as the prion protein associated with Creutzfeldt-Jakob disease [76]. This ‘Aβ channel’ has been widely investigated in lipid bilayers, allowing for the biophysical and pharmacological characterization of the channel. Aβ has been shown

Concluding remarks

Converging evidence from a variety of experimental systems supports an important and proximal pathological role for calcium dyshomeostasis in AD. Despite two decades of research, the precise contribution of dysfunctions in calcium signalling to the pathogenesis of this disease remains unclear. It is well established that Aβ is neurotoxic, and through the advent of transgenic technology there is growing evidence that cognitive dysfunction occurs prior to neuronal cell loss yet correlates with

Acknowledgements

This work was supported by grants from the National Institutes of Health (AG17968 and AG16573). We thank Dr. Lauren Billings and Mr. Brain Hitt for critically reading the manuscript.

References (109)

  • P.A. Barrow et al.

    Functional phenotype in transgenic mice expressing mutant human presenilin-1

    Neurobiol. Dis.

    (2000)
  • A. Parent et al.

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

    Neurobiol. Dis.

    (1999)
  • S. Oddo et al.

    Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction

    Neuron.

    (2003)
  • R. Etcheberrigaray et al.

    Calcium responses in fibroblasts from asymptomatic members of Alzheimer's disease families

    Neurobiol. Dis.

    (1998)
  • A.M. Thomson

    Facilitation, augmentation and potentiation at central synapses

    Trends Neurosci.

    (2000)
  • F. Kamenetz et al.

    APP processing and synaptic function

    Neuron

    (2003)
  • J. Herms et al.

    Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein

    J. Biol. Chem.

    (2003)
  • Y. Akbari et al.

    Presenilin regulates capacitative calcium entry dependently and independently of gamma-secretase activity

    Biochem. Biophys. Res. Commun.

    (2004)
  • S.M. Fitzjohn et al.

    Calcium stores and synaptic plasticity

    Cell Calcium

    (2002)
  • C.S. Casley et al.

    Beta-amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons

    Neurobiol. Dis.

    (2002)
  • R.M. Davidson et al.

    Amyloid beta-peptide Aβ potentiates a nimodipine-sensitive L-type barium conductance in N1E-115 neuroblastoma cells

    Brain Res.

    (1994)
  • F.J. Ekinci et al.

    Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration

    J. Biol. Chem.

    (1999)
  • C. Lu et al.

    The lipid peroxidation product 4-hydroxynonenal facilitates opening of voltage-dependent calcium channels in neurons by increasing protein tyrosine phosphorylation

    J. Biol. Chem.

    (2002)
  • A. MacManus et al.

    Enhancement of (45)calcium influx and voltage-dependent calcium channel activity by beta-amyloid-(1–40) in rat cortical synaptosomes and cultured cortical neurons. Modulation by the proinflammatory cytokine interleukin-1beta

    J. Biol. Chem.

    (2000)
  • M. Kawahara et al.

    Alzheimer's beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line

    J. Biol. Chem.

    (2000)
  • M. Kawahara et al.

    Alzheimer's disease amyloid beta-protein forms Zn2+-sensitive, cation-selective channels across excised membrane patches from hypothalamic neurons

    Biophys. J.

    (1997)
  • S.K. Rhee et al.

    Amyloid beta protein-(1–42) forms calcium-permeable, Zn2+-sensitive channel

    J. Biol. Chem.

    (1998)
  • S.C. Taylor et al.

    Hypoxic enhancement of quantal catecholamine secretion. Evidence for the involvement of amyloid beta-peptides

    J. Biol. Chem.

    (1999)
  • A. Demuro et al.

    Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers

    J. Biol. Chem.

    (2005)
  • G.E. Gibson et al.

    Calcium stores in cultured fibroblasts and their changes with Alzheimer's disease

    Biochim. Biophys. Acta

    (1996)
  • G.E. Gibson et al.

    Diminished mitogen-induced calcium uptake by lymphocytes from Alzheimer patients

    Biol. Psychiatry

    (1987)
  • N. Hirashima et al.

    Calcium responses in human fibroblasts: a diagnostic molecular profile for Alzheimer's disease

    Neurobiol. Aging

    (1996)
  • C. Peterson et al.

    Altered response of fibroblasts from aged and Alzheimer donors to drugs that elevate cytosolic free calcium

    Neurobiol. Aging

    (1988)
  • Y.H. Suh et al.

    Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease

    Pharmacol. Rev.

    (2002)
  • A. Alzheimer, About a peculiar disease of the cerebral cortex. Translated 1987 by L. Jarvik and H. Greenson. Alzheimer...
  • K. Ogomori et al.

    Beta-protein amyloid is widely distributed in the central nervous system of patients with Alzheimer's disease

    Am. J. Pathol.

    (1989)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)
  • D.L. Price et al.

    Alzheimer's disease: genetic studies and transgenic models

    Annu. Rev. Genet.

    (1998)
  • F.M. LaFerla

    Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease

    Nat. Rev. Neurosci.

    (2002)
  • M. Shoji et al.

    Production of the Alzheimer amyloid beta protein by normal proteolytic processing

    Science

    (1992)
  • S. Lammich et al.

    Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease

    Proc. Natl. Acad. Sci. USA

    (1999)
  • R. Vassar et al.

    Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

    Science

    (1999)
  • S. Sinha et al.

    Purification and cloning of amyloid precursor protein beta-secretase from human brain

    Nature

    (1999)
  • D. Levitan et al.

    PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signalling

    Proc. Natl. Acad. Sci. USA

    (2001)
  • B. De Strooper et al.

    Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

    Nature

    (1998)
  • J.T. Jarrett et al.

    The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease

    Biochemistry

    (1993)
  • C.C. Glabe

    Amyloid accumulation and pathogensis of Alzheimer's disease: significance of monomeric, oligomeric and fibrillar Abeta

    Subcell. Biochem.

    (2005)
  • R. Sherrington et al.

    Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease

    Nature

    (1995)
  • E. Levy-Lahad et al.

    Candidate gene for the chromosome 1 familial Alzheimer's disease locus

    Science

    (1995)
  • D.J. Selkoe et al.

    Deciphering the genetic basis of Alzheimer's disease

    Annu. Rev. Genomics Hum. Genet.

    (2002)
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