Surprising Target for Potential AD Agents

The aggregation of insoluble amyloid fibrils is an important pathologic hallmark of Alzheimer's disease (and a number of other conditions). The most fibrillogenic isoform of amyloid beta, Aβ42, is produced when the enzyme γ-secretase cleaves the transmembrane portion of amyloid precursor protein (APP). Therefore a potential strategy for the treatment of AD is the inhibition of γ-secretase with γ-secretase modulators (GSMs).

In this week's issue of Nature, Kukar and colleagues report the surprising finding that the target of their synthetic GSMs is the substrate APP and not the enzyme itself. Specifically the GSM binding site localizes to the 28-36 residue portion of amyloid beta, a region that is critical for amyloid aggregation. Therefore certain GSMs have the potential to suppress the production of Aβ42 and its aggregation. The authors propose that substrate-targeting GSMs for further investigation can be identified by their ability to bind Aβ and APP. One Aβ42-lowering GSM, tarenflurbil (Flurizan; Myriad), is in phase 3 clinical study in patients with mild AD.

The goal of suppressing Aβ42 formation, however, is at odds with recent population studies, which showed that the risk reduction of AD with NSAIDs is not dependent on the suppression of Aβ42. In an e-mail, Kukar acknowledged the disconnect but also stressed that epidemiologic studies cannot substitute for well-controlled clinical trials.

Image of wild-type APP (left) and amyloid fibril (right) by David S. Goodsell from Wikimedia Commons.