Oxidative Stress May Have Key Role in Parkinson’s Dementia, Study Finds

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An increase in a type of cellular damage called oxidative stress in certain brain regions may be the reason dementia develops in people with Parkinson’s disease, according to a study in rat models.

The study, “Investigating key factors underlying neurodegeneration linked to alpha-synuclein spread,” was published in Neuropathology and Applied Neurobiology.

Parkinson’s is caused by the death and dysfunction of brain cells that make the chemical messenger dopamine, particularly in a region called the substantia nigra or SN. Most people with Parkinson’s will develop dementia or other cognitive impairments, which may be linked with damage in other parts of the brain.

However, the precise biological mechanisms underlying cognitive issues in Parkinson’s remain incompletely understood.

At the molecular level, Parkinson’s is characterized by the formation of aggregates, or clumps, of the protein alpha-synuclein. It has been well-established that alpha-synuclein aggregates can propagate throughout the brain; clumps in one brain region spur clumps to form in other brain regions.

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Oxidative stress and Parkinson’s dementia

A team led by scientists in China conducted a series of experiments that began with injecting alpha-synuclein aggregates into the brains of rats, specifically in a region called the medial forebrain bundle (MFB) that is highly interconnected with other brain regions. They then examined the spread of alpha-synuclein at 60, 90, and 120 days post-injection

After injection, higher levels of phosphorylated alpha-synuclein — the version of the protein mainly responsible for forming aggregates — were seen in the SN region, and also in the frontal cortex and hippocampus. These two brain regions, involved in thinking and memory, are affected in people with dementia.

Despite the toxic protein’s spread, the researchers found minimal signs of neurological damage in the frontal cortex or hippocampus. Some damage was noted in the substantia nigra, but it was only apparent at the latest time point assessed.

Some motor deficits were evident in rats injected with alpha-synuclein, though again only at later time points when SN damage was also notable. The rats did not show issues with cognition or memory.

The team then conducted a battery of similar experiments, but instead of injecting the rats’ forebrain region or MFB with alpha-synuclein, they injected 6-hydroxydopamine (6-OHDA), a chemical that is highly toxic to dopamine-making cells. Injections of 6-OHDA have been used for decades to create a Parkinson’s model.

An uptick in phosphorylated alpha-synuclein levels was seen in the frontal cortex and hippocampus following the injection. Increased levels of phosphorylated tau — another clumping protein that is mainly associated with Alzheimer’s disease — also were noted after 6-OHDA injection, but not after alpha-synuclein injection.

Injections of 6-OHDA led to potent cell death in the SN, and abnormalities indicating nerve degeneration also were noted in the frontal cortex but not in the hippocampus. Compared with rats injected with alpha-synuclein, rats given 6-OHDA had more pronounced motor problems, and they also showed marked impairment in assessments of learning and memory.

Further examination of the rats’ brains found a marked increase in oxidative stress in the substantia nigra, frontal cortex, and hippocampus following 6-OHDA injection, none of which was seen following alpha-synuclein injection. Oxidative stress is a type of cell damage caused by highly reactive oxygen-containing molecules. Increases in a similar type of cell damage called nitrative stress also were noted following 6-OHDA injection.

“Taken together, these data may suggest that in the absence of an oxidative stress response, [aggregated alpha-synuclein] may not be sufficient to induce rapid and major neurodegenerative changes in the frontal cortex and the hippocampus, despite the presence of phosphorylated” alpha-synuclein spreading to these brain regions, the researchers concluded.

Based on these findings, the team postulated that greater oxidative/nitrative stress in regions important for learning and cognition may play a central role in dementia affecting people with Parkinson’s.

“We therefore propose that future therapeutic interventions to slow or prevent the conversion of [Parkinson’s disease] to PDD [Parkinson’s disease dementia] may be through the reduction of oxidative/nitrative stress,” they wrote.

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