The role of amyloid precursor protein processing by BACE1, the beta-secretase, in Alzheimer disease pathophysiology

Abstract

Amyloid plaques, composed of the amyloid beta-protein (Abeta), are hallmark neuropathological lesions in Alzheimer disease (AD) brain. Abeta fulfills a central role in AD pathogenesis, and reduction of Abeta levels should prove beneficial for AD treatment. Abeta generation is initiated by proteolysis of amyloid precursor protein (APP) by the beta-secretase enzyme BACE1. Bace1 knockout (Bace1(-/-)) mice have validated BACE1 as the authentic beta-secretase in vivo. BACE1 is essential for Abeta generation and represents a suitable drug target for AD therapy, especially because this enzyme is up-regulated in AD. However, although initial data indicated that Bace1(-/-) mice lack an overt phenotype, the BACE1-mediated processing of APP and other substrates may be important for specific biological processes. In this minireview, topics range from the initial identification of BACE1 to the fundamental knowledge gaps that remain in our understanding of this protease. We address pertinent questions such as putative causes of BACE1 elevation in AD and discuss why, nine years since the identification of BACE1, treatments that address the underlying pathological mechanisms of AD are still lacking.

FIGURE 1.

Amyloidogenic APP processing. BACE1 and the γ-secretase complex (here depicted as PS, but known to also comprise APH1, NCT, and PEN2 (1)) sequentially cleave APP to generate Aβ. BACE1 cleavage of APP is a prerequisite for γ-secretase APP cleavage. BACE1 initiates Aβ genesis, and this scission liberates the Aβ N terminus, together with APPsβ and C99. C99 forms the γ-secretase substrate, which it cleaves to yield Aβ and an AICD. Monomeric, oligomeric, and fibrillar forms of Aβ are detectable in AD brain.