ACE levels are lower. Which functions have changed?

A study has examined how ACE, an enzyme involved in blood pressure regulation, relates to psychosis.

A Johns Hopkins research team found lower ACE protein levels in the serum and cerebrospinal fluid of patients with early-stage psychosis. Serum levels were lower still in patients classified as having treatment-resistant psychosis. Yet enzyme activity measured per unit volume of serum did not differ significantly between patients and healthy controls. Original paper ↗

Lower ACE abundance does not necessarily mean weaker catalytic function. The researchers suggest that a role beyond its established enzymatic functions could be involved in the disease process. They have not, however, identified that role. Research institution's explanation ↗

ACE has already been studied in relation to depression. In chronically stressed mice, the ACE inhibitor captopril improved depression-like behaviors, with evidence implicating bradykinin-dependent changes in neuronal function. This was not a demonstration of a nonenzymatic role for ACE. Mouse study ↗ Human observational studies have linked the use of some ACE inhibitors to a lower incidence of depression, while other research has found no protective association with ACE inhibitors or angiotensin receptor blockers. These findings do not establish ACE inhibitors as a treatment for depression, but there is an experimental foundation for investigating ACE's roles in the brain. Danish observational study ↗, Study in older adults with hypertension ↗

The question we would pursue is what happens to neurons and circuits when ACE protein abundance, catalytic activity, and localization are examined separately.

For example, does restoring ACE abundance in patient-derived cells change their state? Would ACE that lacks catalytic activity produce the same change? Conversely, what happens when catalytic activity is altered while protein abundance is maintained? Localization, including at the cell membrane, and differences in molecular interaction partners are also worth investigating.

These questions merit investigation in mice as well as cells. Examining how changes in ACE abundance or function affect neural circuit activity and behavioral measures could take the associations observed in patients toward tests of causality. Effects arising from changes in blood pressure or locomotor activity would also need to be distinguished. These experiments were not performed in the present study; they are proposals for further research based on its findings.

The availability of antihypertensive drugs that target ACE provides a starting point. But suppressing catalytic activity with an existing drug is not the same as changing protein abundance or localization. If a particular ACE inhibitor fails to improve symptoms, that alone is not a reason to exclude ACE from investigation of the disease process. If symptoms do improve, the mechanism responsible still needs to be established.

The present study concerns early-stage psychosis; it is not a trial of antihypertensive treatment for depression. Nor does the absence of a significant difference in serum activity establish that catalytic function is unchanged in particular brain cells or regions.

The findings raise more than the question of whether an ACE inhibitor works. Investigating why protein abundance and measured activity do not change in parallel may reveal roles for ACE that have not yet been captured. We see this study as a basis for testing observations from patients in cells and mice.