Intracellular Signalling in Alzheimer’s Disease

Alzheimer’s disease is a progressive and irreversible neurodegenerative disorder that leads to cognitive, memory and behavioural impairments.Most cases of Alzheimer’s disease are IDIOPATHIC, and advanced age and inheritance of the ε4 allele of the POLYMORPHIC apolipoprotein E gene (APOE) serve as major risk factors, although neither is sufficient to cause the disease1. A small percentage of cases are inherited in a Mendelian (autosomal dominant) fashion. These are referred to as familial Alzheimer’s disease (FAD), and are generally distinguished from most sporadic cases by the emergence of clinical symptoms earlier than the seventh decade of life.Despite the disparity in age of onset,both forms share common histopathological features: the extracellular deposition of diffuse and neuritic plaques that are composed of amyloid-β (Aβ) peptide, the intracellular accrual of neurofibrillary tangles that consist of hyperphosphorylated aggregates of the microtubuleassociated protein TAU, and selective neuronal loss. These histopathological lesions do not occur diffusely throughout the brain, but are restricted to selective regions,particularly the hippocampus and neocortex. 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 disease2. 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 DYSHOMEOSTASIS AND INTRACELLULAR SIGNALLING IN ALZHEIMER’S DISEASE