Keqiang Ye’s lab at Emory recently published a paper in Nature Communications that offers a two for one deal in Alzheimer’s drug discovery.
Periodically we hear suggestions that the amyloid hypothesis, the basis of much research on Alzheimer’s disease, is in trouble. Beta-amyloid is a toxic protein fragment that accumulates in extracellular brain plaques in Alzheimer’s, and genetics for early-onset Alzheimer’s point to a driver role for amyloid too.
Unfortunately, anti-amyloid agents (either antibodies that sop up beta-amyloid or drugs that steer the body toward making less of it) have not shown clear positive effects in clinical trials.
That may be because the clinical trials started too late or the drugs weren’t dosed/delivered right, but there is a third possibility: modifying amyloid by itself is not enough.
Ye’s lab has been investigating an enzyme called AEP (asparagine endopeptidase), which he provocatively calls “delta secretase.” AEP is involved in processing both amyloid and tau, amyloid’s intracellular tangle-forming counterpart.
Ye’s March 2017 Nature Communications paper shows that in mice, an inhibitor of AEP has positive effects in amyloid- and tau-based Alzheimer’s models, both in terms of staving off accumulation of the toxic proteins and in protecting brain cell function.
To be sure, Alzheimer’s drug discovery efforts have gone well at the mouse stage only to falter later, and targeting AEP may not tackle other factors such as inflammation or lipid metabolism. Still, it’s a way to hit two birds – amyloid and tau — with one stone. Pursuing AEP may be relevant in other neurodegenerative diseases such as frontotemporal dementia that are clearly tau-driven.