Alzheimer's disease is the leading cause of dementia, afflicting about 5% of the population over the age of 65, and 33–50% of those over 80. At present, there is no cure for this insidious disorder. Given that life expectancy in many populations is being extended, Alzheimer's disease will remain a huge clinical and economic burden for many societies.
A small percentage of cases of Alzheimer's disease are inherited in an autosomal-dominant fashion. At the neuropathological level, the familial and the more common sporadic cases are virtually indistinguishable. The age of onset is the main distinguishing feature between the two; in familial Alzheimer's disease, onset is generally earlier than the seventh decade.
Most familial cases result from missense mutations in the presenilin 1 (PS1) and PS2 genes, which lead to increased formation of the highly amyloidogenic amyloid-β peptide Aβ1–42. There is compelling evidence that presenilin might be the catalytic subunit of the γ-secretase complex, which is crucial for the formation of Aβ, although this is not universally accepted.
Disruption of calcium homeostasis is another feature that is always associated with clinical mutations in the presenilin genes. Mutations of both PS1 and PS2 disrupt the phosphoinositide signalling cascade, indicating that the destabilization of calcium homeostasis is a pathogenic pathway that is common to both PS1 and PS2.
An elevation of calcium-store content in the endoplasmic reticulum seems to be one mechanism by which presenilin mutations disrupt intracellular calcium signalling. In addition, capacitive calcium entry, which is a process for replenishing depleted calcium stores in the endoplasmic reticulum, is attenuated by presenilin mutations.
Some of the presenilin-dependent effects on calcium signalling are mediated by a γ-secretase-derived product. The amyloid precursor protein (APP) intracellular domain (AICD) regulates phosphoinositide-mediated calcium signalling through a γ-secretase-dependent signalling pathway. The intramembraneous proteolysis of APP has a signalling function that is analogous to that of Notch.
Calcium dysregulation is a crucial and proximal component of the pathogenesis of Alzheimer's disease, and is capable of eliciting the characteristic lesions of this disorder, including increased Aβ formation, the hyperphosphorylation of TAU and neuronal cell death.
Calcium modulates many neural processes, including synaptic plasticity and apoptosis. Dysregulation of intracellular calcium signalling has been implicated in the pathogenesis of Alzheimer's disease. Increased intracellular calcium elicits the characteristic lesions of this disorder, including the accumulation of amyloid-β, the hyperphosphorylation of TAU and neuronal death. Conversely, neurodegeneration that is induced by amyloid-β or TAU is probably mediated by changes in calcium homeostasis. Disruption of calcium regulation in the endoplasmic reticulum mediates the most significant signal-transduction cascades that are associated with Alzheimer's disease. Moreover, mutations that cause familial Alzheimer's disease have been linked to intracellular calcium signalling pathways. Destabilization of calcium signalling seems to be central to the pathogenesis of Alzheimer's disease, and targeting this process might be therapeutically beneficial.
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I thank M. Leissring and Y. Akbari for their contributions to the original work cited in this manuscript, and F. Van Leuven for discussing unpublished work. I also thank K. Stauderman, C. Glabe, K. Street, G. Stutzmann, J. Shepherd and B. Tseng for critically reading the manuscript, and I. Parker for providing figure 1. Work in my laboratory is supported by grants from the US Public Health Service, the American Health Assistance Foundation and the American Federation of Aging Research.
Encyclopedia of Life Sciences
Arising spontaneously or from an unknown cause.
Occurring in multiple forms. For example, the APOE gene exists as three variants: APOE2, APOE3 and APOE4.
- OX-2 ANTIGEN DOMAIN
An antigen domain that is recognized by antibodies to lymphocytes. A member of the immunoglobulin superfamily of cellular adhesion molecules, OX-2 has a major role in the activation of lymphocytes and macrophages.
- KUNITZ PROTEASE-INHIBITOR DOMAIN
A functional domain that is common to a large family of proteins — including APP, aprotinin and noggin — that inhibits serine proteases such as trypsin.
The full-length, native polypeptide before proteolytic cleavage events that might occur during maturation.
- G PROTEIN
A heterotrimeric GTP-binding and -hydrolysing protein that interacts with cell-surface receptors, often stimulating or inhibiting the activity of a downstream enzyme. G proteins consist of three subunits: the α-subunit, which contains the guanine-nucleotide-binding site; and the β- and γ-subunits, which function as a βγ heterodimer.
- ATOMIC FORCE MICROSCOPY
A form of microscopy in which a probe is mechanically tracked over a surface of interest in a series of x–y scans. The force found at each coordinate is measured with piezoelectric sensors, providing information about the chemical nature of a surface.
- CAPACITATIVE CALCIUM ENTRY
Calcium influx that occurs in response to the depletion of intracellular calcium stores. Calcium enters the cell through specialized store-operated channels in the plasma membrane, allowing depleted calcium stores in the endoplasmic reticulum to be replenished.
A substance (natural or synthetic, cyclic or linear) that can bind metal ions in solution and transport them across lipid barriers in natural or artificial membranes.
- SERCA PUMP
The sarco-/endoplasmic reticulum calcium ATPase — a pump in the membrane of the endoplasmic reticulum that replenishes calcium stores.
Existing in more than one geographical region.
- TYPE 1 TRANSMEMBRANE PROTEIN
An integral membrane polypeptide that extends across the lipid bilayer once, as a single α-helix.
The hyperpolarization that ensues after strong depolarization of the membrane.
- DOMINANT NEGATIVE
Describes a defective protein that retains interaction capabilities and so distorts or competes with normal proteins.
- ADAPTOR PROTEIN
A protein that augments cellular responses by recruiting other proteins to a complex. Adaptor proteins usually contain several protein–protein-interaction domains.
A sequence that contains all of the elements — such as the alternative exons and the surrounding introns — that are necessary to show the same splicing pattern as the endogenous gene.
Able to produce two or more unrelated effects.
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LaFerla, F. Calcium dyshomeostasis and intracellular signalling in alzheimer's disease. Nat Rev Neurosci 3, 862–872 (2002). https://doi.org/10.1038/nrn960
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