Figure 122

Generation of Afi42 from APP.

There is cumulative evidence that Afi, in particular the Afi422 variant, plays a significant role in the pathogenesis of AD, thus forming the basis of the "amyloid hypothesis."21 This hypothesis predicts that reducing cerebral Afi levels should prevent or stop the progression of AD and provides a broad framework to formulate a drug discovery strategy, including either inhibition of Afi production or aggregation, enhancement of its clearance or degradation, or a combination of these approaches.

Considering the amyloid hypothesis as the basis of AD drug discovery, Afi represents a relevant and measurable end point. Although many questions remain unanswered, recent advances have given us important insights regarding the regulation of Afi production and degradation, the dynamics of its aggregation, and the cellular mechanism of its neurotoxicity. In the continuum from the initial proteolytic processing of APP to accumulation of plaques, there are a multitude of steps that can regulate the steady-state levels of Afi in the brain and thus, potentially, represent points of therapeutic intervention. Figure 12.3 schematically depicts this cascade, with each step presenting different opportunities and challenges for drug discovery.

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