The secrets of a new Alzheimer's secretase

The title of Keqiang Ye’s recent Nature Communications paper contains a provocative name for an enzyme: delta-secretase. Dr. Ye is a faculty member in the MSP and NS programs.

Just from its name, one can tell that a secretase is involved in secreting something. In this case, that something is beta-amyloid, the toxic protein fragment that tends to accumulate in the brains of people with Alzheimer’s disease.

This enzyme previously was called AEP, for asparagine endopeptidase. AEP appears to increase activity in the brain with aging and cleaves APP (amyloid precursor protein) in a way that makes it easier for the real bad guy, beta-secretase, to produce bad beta-amyloid.

Ye’s lab originally had probed AEP’s function in the context of cell death and DNA damage in stroke. Working with Emory ADRC colleagues such as NS faculty member Allan Levey and BCDB and NS faculty member Nick Seyfried, they went on last year to show in Nature Medicine that AEP also snips the neurofibrillary tangle protein tau in a way that may promote pathology.

The current paper makes AEP a potential Alzheimer’s drug target that is involved in the accumulation of two of the disease’s troublemaker proteins, tau and beta-amyloid. It also addresses debate in the field (see comments at end) about where AEP can be found in the cell. Ye reports his team is screening compounds that inhibit AEP as potential drug candidates.

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