High RAS Antibody Levels May Drive Disease, But Medicines Exist

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Antibodies against certain components of the renin-angiotensin system (RAS), which helps to control blood pressure, are present at higher levels in people with Parkinson’s than in those without the disease and may drive progression, a study found.

These elevated levels of autoantibodies — which make nerve cells more vulnerable to degeneration — and of inflammation markers both returned to a normal range upon treatment with an approved blood pressure medication: an angiotensin receptor blocker called candesartan (sold as Atacand, among other names).

“The results suggest dysregulation of RAS autoantibodies as a new mechanism that can contribute to [Parkinson’s disease] progression,” the researchers wrote, adding that “therapeutical strategies blocking the production, or the effects of these autoantibodies may be useful for [Parkinson’s disease] treatment.”

The study, “Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson’s disease,” was published in the journal npj Parkinson’s Disease.

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An imbalance in the components of the renin-angiotensin system, or RAS, is thought to contribute to the development of Parkinson’s by making neurons stressed and inflamed.

Most components of this system can be divided into two branches that act against each other: one contains angiotensin 2 and its type 1 (AT1) receptors, which are pro-oxidative and pro-inflammatory; the other contains angiotensin 2 and its type 2 (AT2) receptors, which have opposite effects.

A protein called angiotensin-converting enzyme 2 (ACE2) acts as a one-way bridge between the two branches by converting a pro-inflammatory component into an anti-inflammatory one. Together, they help to control blood pressure and the workings of kidneys and heart.

But the body sometimes makes antibodies against its own RAS. These autoantibodies can cause an imbalance in the system’s components.

A team of researchers in Spain set out to study whether such autoantibodies may play a role in how Parkinson’s develops. The scientists focused on autoantibodies against AT1 and ACE2.

Their study included 117 patients with Parkinson’s (60 women and 57 men, mean age of 69.4) and 106 healthy adults as controls (55 women and 51 men, mean age of 64.9).

The researchers began by collecting blood samples from both groups to obtain serum, which is the clear liquid part of the blood that remains after its blood cells and clotting proteins are removed.

Measures of the median serum levels of AT1 and ACE2 autoantibodies showed both to be higher in patients than in controls (8.92 vs. 7.56 units/ml for AT1 and 13.52 vs. 6.30 units/ml for ACE2 autoantibodies).

Furthermore, the chance of a person receiving a Parkinson’s diagnosis increased by 7.4% per unit of concentration of AT1 autoantibodies. The increased risk per unit concentration of ACE2 autoantibodies was 1.9%. Each year’s addition to age also increased a diagnostic chance by between 4.7% and 6.4%.

In patients and controls, both autoantibody levels correlated positively, meaning that the higher the serum levels of AT1 autoantibodies, the higher those of ACE2 autoantibodies. AT1 autoantibody levels in patients also correlated positively with some pro-inflammatory molecules.

Four patients who underwent a lumbar puncture had cerebrospinal fluid (CSF) — the fluid that surrounds the brain and the spinal cord — samples for evaluation, as did five healthy controls. Both autoantibodies were present in the patients’ CSF, and at higher levels than found in the control samples, the researchers reported.  But they noted that this finding should be interpreted with caution due to the limited samples available, although it did “agree with the observations” in animal work that followed.

A rat model of Parkinson’s was created by injecting a toxic compound called 6-hydroxydopamine into some animals’ forebrain to kill neurons, while other rats were given a saline injection to serve as controls. The rats were then evaluated to determine the  AT1 and ACE2 autoantibodies on neuronal degeneration.

Levels of AT1 and ACE2 autoantibodies, measured in the animals’ serum and CSF at 10 days and four weeks post-injection, were significantly higher for both measures in Parkinson’s rats than control rats, supporting a link with nerve cell loss.

“This [increase] suggests that the autoantibody production is related to neuron death and neuroinflammation,” the researchers wrote. In Parkinson’s patients, they added, “an initial death of dopaminergic neurons and/or the corresponding neuroinflammatory process may induce AT1-AA and ACE2-AA [AT1 and ACE2 autoantibodies], which may contribute to progression of the disease during the long period of active cell death and neuroinflammation.”

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Neurons isolated from rats were also grown in the lab, and then given both 6-hydroxydopamine and AT1 pro-inflammatory autoantibodies. This was done to find out whether these autoantibodies enhanced the toxic effects of 6-hydroxydopamine on dopaminergic nerve cells.

Compared to 6-hydroxydopamine alone, the combination of 6-hydroxydopamine and AT1 autoantibodies increased the number of dead neurons. It also caused a rise in markers of inflammation.

Adding candesartan, an angiotensin 2 receptor antagonist that blocks the action of angiotensin 2, prevented a worsening in neuronal viability due to the AT1 autoantibodies.

“AT1 autoantibodies enhanced dopaminergic neuron degeneration and increased levels of neuroinflammation markers, which was inhibited by the AT1 antagonist candesartan,” the researchers wrote.

Study results “show that levels of serum AT1-AA (AT1 receptor agonists) and ACE2-AA (ACE2 antagonists) are significantly higher in PD [Parkinson’s disease] patients than in non-PD controls, possibly as a consequence of the dopaminergic degeneration and the corresponding neuroinflammatory changes. Together with age, a well-known risk factor for PD, both AT1-AA and ACE2-AA had a positive association” with the disease, the scientists concluded.

While the mechanisms linking these antibodies with Parkinson’s “remain to be fully clarified,” these findings “suggest for the first-time autoantibodies against AT1 receptors and ACE2 as a new mechanism of progression of dopaminergic degeneration and neuroinflammation” in Parkinson’s, they added.

Results also “further support repurposing AT1 blockers (ARBs) as treatment against PD progression.”

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