Abstract
Amyloid plaques, hallmark neuropathological lesions in Alzheimer’s disease (AD) brain, are composed of the β-amyloid peptide (Aβ). A large body of evidence suggests Aβ is central to the pathophysiology of AD and is likely to start this intractable neurodegenerative disorder. Mutations in three genes (amyloid precursor protein/APP, presenilin1, presenilin2) cause early on-set familial AD by increasing synthesis of the toxic 42 amino acid species of Aβ (Aβ42). Fibrillar Aβ in amyloid plaques appears to cause neurodegeneration, although recent studies suggest soluble Aβ oligomers may also be neurotoxic. Regardless, given the strong correlation between Aβ and AD, therapeutic strategies to lower cerebral Aβ levels should prove beneficial for the treatment of AD. Aβ is derived from APP via cleavage by two proteases, β- and γ-secretase. β-secretase, recently identified as the novel aspartic protease BACE1, initiates the formation of Aβ. Consequently, BACE1 in principle is an excellent therapeutic target for strategies to reduce the production of Aβ in AD. However, the discovery of the homologue BACE2 raised the question of whether it too may be a β-secretase. To settle this issue, our group and others have used gene targeting to generate BACE1 deficient (knockout) mice. These BACE1 knockout mice have been instrumental in validating BACE1 as the authentic β-secretase in vivo. Here, I review the roles of BACE1, APP, and Aβ in AD and discuss the implications of therapeutic approaches that target BACE1 for the treatment of AD.
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Vassar, R. (2005). β-Secretase, APP and Aβ in Alzheimer’s Disease. In: Harris, J.R., Fahrenholz, F. (eds) Alzheimer’s Disease. Subcellular Biochemistry, vol 38. Springer, Boston, MA . https://doi.org/10.1007/0-387-23226-5_4
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