Protein structures in Alzheimer's disease: The basis for rationale therapeutic design

Alzheimer's disease (AD) is a neurodegenerative disorder that affects memory, behavior, thinking and emotion. Current therapies to treat AD patients are only capable for temporarily slowing-down the cognitive decline, as they are focused on ameliorating symptoms instead of targeting its underlying causes. The aim of this review is to describe what is known about the protein structures implicated in AD pathogenesis, amyloid cascade members, as well as those structures involved in Aβ clearance. Thus, structural information available for APP, α- β- and γ-secretases, CTFβ and derived Aβ peptides, AICDs, apoE and apoJ, LRP-1 and RAGE, and neprilysin and insulin-degrading enzyme is provided. The recently solved structure for the γ-secretase complex opens the rational design of a new generation of inhibitors, whereas that for Aβ oligomers offers a putative mechanism explaining why monoclonal antibodies targeted to the N-terminus are effective. Then, an overview on therapies targeting some of these molecules presents their benefits and drawbacks. As a general conclusion our knowledge on the protein structures involved in AD has recently substantially advanced, allowing for the rational design of different therapeutic approaches. Hopefully, we are getting closer to finding a strong disease-modifying drug to cure this devastating disease.