%0 Journal Article %T Presenilins and the ¦Ã-secretase: still a complex problem %A David H Small %A David W Klaver %A Lisa Foa %J Molecular Brain %D 2010 %I BioMed Central %R 10.1186/1756-6606-3-7 %X 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-¦Â protein (A¦Â) which is derived by proteolytic cleavage from a much larger amyloid-¦Â precursor protein (APP) [3]. A¦Â displays a spontaneous ability to aggregate into oligomers and larger fibrillar structures, and it is generally thought that the accumulation of oligomeric A¦Â is chiefly responsible for the neurodegeneration that occurs in AD [4].For the generation of A¦Â, APP is first cleaved on the N-terminal side of the A¦Â sequence by the ¦Â-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 ¦Ã-secretase to yield A¦Â 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 A¦Â possesses 40 amino-acid residues (A¦Â1-40). However, other minor species are also produced which vary in the C-terminal sequence. Production of a longer 42-residue species (A¦Â1-42) is thought to be intimately associated with AD pathogenesis [6]. A¦Â1-42 aggregates more readily than A¦Â1-40, and increased production of A¦Â1-42 may seed aggregation of A¦Â1-40 or other A¦Â 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 %U http://www.molecularbrain.com/content/3/1/7