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The pathogenesis of Alzheimer’s disease is complex, and involves many molecular, cellular and physiological pathologies. The leading candidate for the trigger of Alzheimer’s disease is the Aβ peptide,which is produced by the proteolytic processing of the amyloid precursor protein (APP; BOX 1). Its primacy has been manifested in the ‘amyloid-cascade hypothesis’,which posits that the accumulation of Aβ (resulting from overproduction, altered processing or a failure of clearance mechanisms) is the initiating molecular event that triggers neurodegeneration in sporadic and familial Alzheimer’s disease. The most compelling evidence in support of this hypothesis emerged from advances in our understanding of the molecular and cell biology of genes that either directly cause or enhance the risk for Alzheimer’s disease, as they all modulate some facet of the formation or stability of Aβ.However, the same logic can be used to support the proposal of an early, central role for calcium dysregulation in the pathogenesis of Alzheimer’s disease.
Every gene that is known to increase susceptibility to Alzheimer’s disease also modulates some aspect of calcium signalling. That calcium dysregulation is involved in the neurodegeneration of Alzheimer’s disease is irrefutable. The unresolved and crucial question is whether it is an upstream component or a downstream sequela of the disease. This review focuses on the significance and role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease.
Calcium dysregulation is involved in the neurodegeneration of Alzheimer’s disease is irrefutable. The unresolved and crucial question is whether it is an upstream component or a downstream sequela of the disease. This review focuses on the significance and role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease. link by which calcium dysfunction can influence the accumulation of Aβ and the hyperphosphorylation of TAU. The first condition is supported by a large body of evidence from human subjects and from experimental models, which has shown that alterations in calcium signalling occur during the initial phases of the disease, and even before the development of overt symptoms5. In addition,many studies that have used primary cells from transgenic embryos for example, from mice with mutations in APP or presenilin 1 (PS1) have found disturbances in calcium signaling months before any obvious extracellular Aβ pathology.
Amounts of Aβ might exert a pathogenic effect.Moreover, one mechanism by which Aβ toxicity is manifested is through the destabilization of calcium regulation, a fact that closely links the two temporally. Although genetic evidence supports an early role for Aβ, it could still be just an epiphenomenon, and a subtler, less obvious molecular defect might be the primary trigger for Alzheimer’s disease. For example, some investigators have suggested that calcium dysfunction or other, unidentified events precede Aβ in the cascade. However, data from my laboratory indicate that alterations in Aβ formation precede the changes in calcium.
The Aβ peptide that is the primary constituent of diffuse and neuritic plaques is derived from the altered processing of APP1. The function of the APP HOLOPROTEIN is unknown, and ablation of the APP gene does not lead to any substantial phenotype in gene-targeted mice. APP is a member of a larger gene family that includes the amyloid-precursor-like proteins APLP1 and APLP2, which compensate for the loss of APP. The combined ablation of APP and APLP2, both APLP genes or all three family members leads to early postnatal lethality, but no functional role for APP has emerged from these studies. More recent evidence supports one of two possible physiological functions of APP in neurons. First,APP might be an axonal transport receptor. This protein binds to the light chain subunit of kinesin 1, a microtubule motor protein.Kinesin-mediated axonal transport of vesicles containing β-site APP-cleaving enzyme (BACE) and PS1 requires APP20.APP can be cleaved by BACE in these vesicles to generate Aβ and a carboxyterminal fragment of APP, which then liberates kinesin.The second likely function of APP is in modulating signal transduction. APP associates with the brain G PROTEIN Go, which is involved in signal transduction, and missense mutations in APP near the γ-secretase site,which cause FAD, lead to the constitutive activation of Go-linked receptors.A signal-transduction pathway might also link APP and apoptosis, as APPinduced cell death involves the activation of a G-proteindependent pathway. In addition,Aβmight activate a G-protein-coupled receptor.Moreover, the recent discoverythat the cytoplasmic carboxyl- terminal domain of APP is transported to the nucleus and modulates calcium signalling provides further evidence that it has a role in signal transduction.This role will be considered in greater detail in this review, particularly with regard to calcium signalling. Two significant interactions between APP metabolism and calcium dynamics need to be considered. The first involves the effects of APP and its metabolic derivatives on cellular calcium homeostasis.The second focuses on the opposite question: the manner by which calcium modulates APP processing, particularly itseffect on Aβ production. Modulation of APP processing by calcium. Although alarge body of work shows that calcium signalling can be disrupted by derivatives of APP, including Aβ, theeffects of calcium destabilization on APP processing have not been thoroughly investigated.Although a few studies have addressed this question, it has not been systematically examined and there are some contradictory reports. The effects of calcium signalling on APP proteolysis are complex, and it is plausible that increased or decreased calcium levels could have incongruent effects on APP processing and Aβ formation and/or release. These effects might depend on diverse factors, such as whether increased cytosolic calcium is released from internal stores (which might affect CAPACITATIVE CALCIUM ENTRY (CCE), for example) or enters through plasma membrane calcium channels, and whether inositol-1,4,5-trisphosphate (Ins(1,4,5)P3)- or ryanodine-sensitive pools are released.
The first study to show that Aβ formation can be modulated by calcium was by Querfurth and Selkoe. They showed that elevating cytosolic calcium levels in HEK293 (human embryonic kidney) cells that overexpressed APP7 by treating them with the calcium IONOPHORE A23187 increased the secretion of Aβ, an effect that was dependent on extracellular calcium levels. They also showed that calcium release from internal stores could enhance Aβ generation, as exposure to caffeine, which causes calcium release mediated by ryanodine receptors (RyRs), increased the production of Aβ. So, calcium influx from external sources or release from internal stores triggers increased Aβ formation. By contrast, other treatments that elevate cytosolic calcium levels seem to diminish the formation of Aβ. Thapsigargin,which irreversibly inhibits the SERCA PUMP and blocks the reuptake of calcium into the endoplasmic reticulum (ER), produces a concentration-dependent depression of Aβ release. Akbari et al.have also shown that inhibiting SERCA activity with thapsigargin diminishes Aβ secretion, whereas promoting SERCA activity enhances Aβ genesis.APP processing clearly involves a complex series of events that can occur in multiple cell compartments. In neurons, for instance, some Aβ42 is formed in the ER. Therefore,APP processingmight be particularly susceptible to manipulations that affect ER calcium signalling.Depletion of ER calcium stores might be more important than increasedcytosolic calcium in modulating APP processing, although further studies are required to elucidate the precise mechanism.
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