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Neurodegenerative Disorders: Alzheimer’s Disease

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Neurodegenerative Disorders: Alzheimer’s Disease
Neurodegenerative Disorders: Alzheimer’s Disease

1. Amyloid Precursor Protein (APP) Alzheimer’s disease (AD) remains a major cause of senile dementia, which is characterised by an impairment of neuronal and synaptic function in addition to the accumulation of β-amyloid plaque and formation of neurofibrillary tangles within distinct portions of the brain (De Strooper and Annaert, 2000). Progression of this distinct pathology of neurodegeneration does not typically vary from patient to patient, beginning in cerebral cortex before targeting the hippocampus, neocortex as well as the sub-cortical nuclei (Braak and Braak, 1995). The role of amyloid precursor protein (APP) in the pathogenesis of Alzheimer’s disease is pivotal. The cleavage of APP by the proteases β and γ- secretase releases β-amyloid (Aβ) peptides which results in aggregation of the peptides due to misfolding to form fibrils of Aβ which comprise the key components of amyloid plaque deposits in the brains of AD patients (Glenner and Wong, 1984). Amyloid precursor protein (APP) is a trans-membrane glycoprotein which normally functions in synapse formation as well as axonal elongation. The protein possesses a small cytoplasmic domain but is composed primarily of a large extracellular domain. Processing of APP in the extracellular domain by α or β- secretase results in the complete removal of the protein’s ectodomain which gives rise to an accumulation of sizeable and soluble derivatives of APP referred to as APPsα of APPsβ in addition to membrane- linked carboxyl-terminal fragments (CTFα and CTFβ). The key β- secretase in neurons is β-site APP cleaving enzyme (BACE1). BACE1 is capable of cleavage at the α-secretase site within the Aβ domain of the APP protein to allow liberation complete Aβ peptides following further processing by γ- secretase (Vassar et al., 1999). The γ- secretase machinery is comprised of a number of proteins such as PEN2, APH1, presenilin and nicastrin which form a complex



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