Calcium dysregulation in Alzheimer's disease: Recent advances gained from genetically modified animals
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)
- et al.
Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome
Neuron.
(2004) - et al.
Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice
Neuron
(2005) - et al.
Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor
J. Biol. Chem.
(1998) - et al.
Identification of a novel aspartic protease (Asp 2) as beta-secretase
Mol. Cell Neurosci.
(1999) - et al.
PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin
J. Biol. Chem.
(2002) - et al.
aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation
Dev. Cell
(2002) - et al.
beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms
J. Biol. Chem.
(1993) - et al.
Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals
J. Biol. Chem.
(1999) - et al.
Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons
J. Biol. Chem.
(2000) - et al.
Stores not just for storage. intracellular calcium release and synaptic plasticity
Neuron
(2001)