Amyloid at the cutting edge: activation of alpha-secretase prevents amyloidogenesis in an Alzheimer disease mouse model

Abstract

The amyloid beta-peptide (A beta peptide) is assumed to play a crucial and early role in the pathogenesis of Alzheimer disease. Thus, strategies for a pharmacotherapy aim at reducing A beta peptide generation, which proteolytically derives from the amyloid precursor protein (APP). The main targets so far have been beta- and gamma-secretase, the two proteases that cleave APP at the N- and C-terminus of the A beta peptide and are thus directly responsible for A beta peptide generation. A different strategy, namely the activation of alpha-secretase, has barely been investigated for its therapeutic potential. alpha-Secretase cleaves within the A beta peptide domain and thus precludes A beta peptide generation. Now, new results demonstrate that activation of alpha-secretase indeed reduces A beta peptide generation and toxicity in vivo.

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.