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Presenilins and the γ-secretase: still a complex problem

DOI: 10.1186/1756-6606-3-7

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Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Typically 5-10% of the population over the age of 65 have dementia, and of these cases, a large percentage have AD [1]. AD is characterised by the presence of proteinaceous deposits in the brain [2]. The extracellular amyloid deposits, which are found in the neuropil (amyloid plaques) and in association with small-medium size cerebral blood vessels (cerebral amyloid angiopathy), are composed of a 4 kDa polypeptide known as the amyloid-β protein (Aβ) which is derived by proteolytic cleavage from a much larger amyloid-β precursor protein (APP) [3]. Aβ displays a spontaneous ability to aggregate into oligomers and larger fibrillar structures, and it is generally thought that the accumulation of oligomeric Aβ is chiefly responsible for the neurodegeneration that occurs in AD [4].For the generation of Aβ, APP is first cleaved on the N-terminal side of the Aβ sequence by the β-site APP cleaving enzyme-1 (BACE1), a transmembrane aspartyl protease [3]. The resulting 99-amino acid residue C-terminal fragment (C99) is then cleaved by the γ-secretase to yield Aβ and a C-terminal APP intracellular domain (AICD) fragment (Fig. 1). The function of the AICD fragment is unclear, although it is thought to have a role in intracellular signalling. For example, AICD may be involved in the regulation of gene transcription, synaptic plasticity and cytoskeletal dynamics [5].The major form of Aβ possesses 40 amino-acid residues (Aβ1-40). However, other minor species are also produced which vary in the C-terminal sequence. Production of a longer 42-residue species (Aβ1-42) is thought to be intimately associated with AD pathogenesis [6]. Aβ1-42 aggregates more readily than Aβ1-40, and increased production of Aβ1-42 may seed aggregation of Aβ1-40 or other Aβ species [4].Approximately 5% of all AD cases are autosomal dominant [7]. Soon after the complete APP sequence was cloned in 1987 [8], it became clear that at le


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