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.

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.

Aficionados of Alzheimer’s research may be familiar with other secretases. Gamma-secretase was the target of some once-promising drugs that failed in clinical trials, partly because they also inhibit Notch signaling, important for development and differentiation in several tissues. Now beta-secretase inhibitors are entering Alzheimer’s clinical trials, with similar concerns about side effects.

Many Alzheimer’s researchers have studied gamma- and beta-secretases, but a review of the literature reveals that so far, only Ye and his colleagues have used the term delta-secretase.

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.*At Alzforum, Jessica Shugart describes the enzyme this way:

Like a doting mother, AEP cuts APP into bite-sized portions for toddler BACE1 [beta-secretase] to chew on, facilitating an increase in beta-amyloid production.

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 Allan Levey and 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.

*In contrast, alpha-secretase is actually a good guy because it diverts precursor protein processing away from beta-amyloid.

Posted on by Quinn Eastman in Neuro Leave a comment

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Quinn Eastman

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