Amyloid at the cutting edge: activation of α-secretase prevents amyloidogenesis in an Alzheimer disease mouse model
J. Clin. Invest. Stefan F. Lichtenthaler, et al. 113:1384 doi:10.1172/JCI21746 [Go to this article.]

Figure 1
Proteolytic processing of APP is divided into an amyloidogenic and an antiamyloidogenic pathway. Amyloidogenic pathway: Cleavage of APP by the protease β-secretase (BACE1) occurs at the N-terminus of the Aβ domain and yields the secreted sAPPβ as well as a C-terminal fragment of APP of 99 amino acids (C99). C99 is further cleaved within its transmembrane domain by γ-secretase, leading to the secretion of the Aβ peptide and the generation of the APP intracellular domain (AICD). The Aβ peptide is prone to aggregation. Aβ peptide oligomers are neurotoxic and lead to an impairment of long-term potentiation (LTP). Finally, large amounts of Aβ peptide are deposited in amyloid plaques, which are the characteristic pathological hallmarks of AD. The consecutive cleavage of APP by β- and γ-secretase constitutes the amyloidogenic pathway as it generates Aβ. Antiamyloidogenic pathway: Cleavage of APP by α-secretase within the Aβ peptide domain yields the neurotrophic and neuroprotective sAPPα. The α-secretase is a member of the ADAM family of metalloproteases. α-Cleavage of APP can be induced upon overexpression of ADAM10 or by the activation of second messenger cascades.