Take five--BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation

Abstract

In 1959, Dave Brubeck and Paul Desmond revolutionized modern jazz music by composing their unforgettable Take Five in 5/4, one of the most defiant time signatures in all music. Of similar revolutionary importance for biomedical and basic biochemical research is the identification of the minimal set of genes required to obtain a deadly time bomb ticking in all of us: Alzheimer's disease. It now appears that one needs to Take Five genes to produce a deadly peptide by a proteolytic mechanism, which paradoxically is otherwise of pivotal importance for development and cell fate decisions.

Figure 1

Generation of Aβ from APP via proteolytic processing by β- and γ-secretase (for details, see text). Aβ aggregates and finally precipitates in amyloid plaques. This event initiates the amyloid cascade resulting in additional intracellular aggregations of the tau protein, which then form tangles (the black structures surrounding the amyloid plaque).

Figure 2

Cleavage sites of α-, β-, and γ-secretase. The Aβ domain is shown in red, the TMD is underlined, and the APP-ICD is shown in blue.