PNA5 targets Parkinson’s cognitive symptoms, may slow decline

26 Nov 2024, 13:15 by Margarida Maia, PhD · Parkinson's News Today

Mice modeling Parkinson’s disease performed better on tests of memory and spatial recognition when given daily under-the-skin injections of PNA5, an experimental ProNeurogen therapy targeting cognitive symptoms — suggesting the treatment’s potential to slow cognitive decline in patients.

In this preclinical study, researchers from the University of Arizona College of Medicine in Tucson also observed that PNA5 reduced inflammation and prevented the loss of nerve cells in the hippocampus, a region in the brain that’s responsible for memory and learning.

According to the scientists, these findings may ultimately lead to the development of new preventive treatments for people with Parkinson’s disease and related disorders.

“With PNA5, we’re targeting cognitive symptoms but, in particular, we’re trying to prevent further degeneration from occurring,” Kelsey Bernard, PhD, the study’s first author, said in a university news story. “By going down the protective route, we can hopefully prevent cognitive decline from continuing.”

Titled “The angiotensin (1–7) glycopeptide PNA5 improves cognition in a chronic progressive mouse model of Parkinson’s disease through modulation of neuroinflammation,” the study was published in the journal Experimental Neurology.

50% to 70% of later-stage patients have cognitive symptoms

One study researcher, Meredith Hay, PhD — a professor of physiology at the University of Arizona and the Evelyn F. McKnight Brain Institute — is the founder and CEO of ProNeurogen, the company that holds exclusive rights to develop brain-penetrant PNA5 for clinical use.

Cognitive decline is a common but often overlooked symptom of Parkinson’s, a disease best known for motor symptoms like tremor and slow movement. However, alongside motor symptoms, many patients experience nonmotor symptoms such as difficulty remembering things and processing thoughts.

According to Lalitha Madhavan, MD, PhD, who led the study, 25% to 30% of people with Parkinson’s already have mild cognitive impairment when they are diagnosed with the disease.

“As the disorder progresses into its later stages, 50% to 70% of patients complain of cognitive problems,” Madhavan said. “The sad part is we don’t have a clear way to treat cognitive decline or dementia in Parkinson’s disease.”

The researchers hope that PNA5, a form of a small protein, may provide such a way.

PNA5 seems to have a possibility of stopping or delaying Parkinson’s progression to some extent and could improve the health of brain cells or prevent cells from dying.

PNA5 is a form of angiotensin (1–7), which binds to and activates the MAS receptor — found across the brain. When activated, the MAS receptor sends signals to reduce inflammation and increase blood flow. This is expected to protect nerve cells and improve memory.

To test PNA5, the researchers turned to a mouse model of Parkinson’s that mimics symptoms of cognitive decline. When treated with PNA5 for two months, these mice performed better than those given a placebo on memory and spatial recognition assessments such as the Novel Object Recognition and Y-maze tests.

The therapy worked by reducing inflammation and preventing the loss of nerve cells in the hippocampus, a brain region that plays a role in the formation and consolidation of memories, as well as in spatial navigation.

“PNA5 seems to have a possibility of stopping or delaying Parkinson’s progression to some extent and could improve the health of brain cells or prevent cells from dying,” Madhavan said.

PNA5 seen to reduce levels of inflammatory protein in mice

What exactly causes cognitive decline in Parkinson’s is unclear, but microglia may play a role. Microglia are the immune cells of the brain, which normally look for harmful substances or sites of damage in brain regions.

However, per Bernard, “in Parkinson’s disease, when they’re constantly activated, microglia can propagate further damage to the surrounding tissue. That’s what we see in Parkinson’s brains, particularly in regions associated with cognitive decline.”

PNA5 reduced the levels of an inflammatory protein called MIP-1beta that microglia can produce and release into the bloodstream.

“This inflammatory chemical can directly interact with neurons [nerve cells] in a region of the brain important for learning and memory,” Bernard said.

According to the researchers, this is the first study to show that PNA5 “can alleviate cognitive dysfunction and neuroinflammation, while blunting the hippocampal neurodegeneration in the context of [Parkinson’s disease dementia].”

Madhavan noted that PNA5 “has already been tried and tested in other models,” and researchers are now hoping that this investigational drug can be further developed into a potential treatment for Parkinson’s cognitive symptoms.

She noted that, however, that if ultimately found to work for people with Parkinson’s, PNA5 would likely be part of a larger regimen of treatments.

“I think about it as a cog in the wheel — there are going to be other drugs that support other aspects of Parkinson’s. Taking multiple drugs is never fun, but it’s a complex condition and there can only be complex solutions,” Madhavan said.