Summary: Researchers have discovered a promising approach to treating Alzheimer’s disease by using dopamine to enhance the activity of brain enzymes that reduce harmful plaques. Conducted in mice, the study shows that dopamine increases the production of neprilysin, which destroys beta-amyloid plaques linked to Alzheimer’s disease.
This discovery opens up hope for new treatments if the results can be reproduced in human trials. The next phase of research will focus on understanding how dopamine regulates neprilysin to develop preventative therapies.
Highlights:
- Role of dopamine: Dopamine may increase the production of neprilysin, an enzyme that breaks down beta-amyloid plaques in the brain, potentially offering a new treatment avenue for Alzheimer’s disease.
- Promising results in mice: In a mouse model of Alzheimer’s disease, treatment with L-DOPA, a dopamine precursor, resulted in reduced plaque formation and improved memory function.
- Future research: Understanding how dopamine regulates neprilysin could pave the way for preventive treatments in preclinical Alzheimer’s disease, although the side effects of L-DOPA must be managed.
Source: RIKEN
A new method to combat Alzheimer’s disease has been discovered by Takaomi Saido and his team at the RIKEN Center for Brain Sciences (CBS) in Japan. Using mice with the disease, the researchers found that dopamine treatment could alleviate physical symptoms in the brain and improve memory.
Published in the scientific journal Scientific signaling The August 6 study examines the role of dopamine in promoting the production of neprilysin, an enzyme that can break down harmful plaques in the brain that are the hallmark of Alzheimer’s disease.
If similar results are obtained in human clinical trials, this could lead to an entirely new way of treating the disease.
The formation of hardened plaques around neurons is one of the first signs of Alzheimer’s disease, often appearing decades before behavioral symptoms such as memory loss are detected. These plaques are formed from fragments of the beta-amyloid peptide that accumulate over time.
In the new study, Saido’s team at RIKEN CBS focuses on the enzyme neprilysin because previous experiments have shown that genetic manipulation that produces excess neprilysin in the brain—a process called upregulation—leads to fewer amyloid-beta plaques and better memory in mice.
While genetically engineering mice to produce neprilysin is useful experimentally, treating people with the disease requires a way to do so with medication. Neprilysin tablets or injections are not an option because it cannot enter the brain through the bloodstream.
So the first step in the new study was to carefully screen many molecules to see which ones can naturally upregulate neprilysin in the right parts of the brain.
The team’s previous research led them to narrow the search to hormones produced by the hypothalamus, and they found that applying dopamine to brain cells grown in a petri dish produced increased levels of neprilysin and reduced levels of free-floating beta-amyloid.
Then the serious experiments began. Using a DREADD system, they inserted tiny, custom receptors into dopamine-producing neurons in the mouse’s ventral tegmental area. By adding a custom drug that matched the mice’s food, the researchers were able to continuously activate these neurons, and only these neurons, in the mice’s brains.
As in the study, activation led to an increase in neprilysin and a decrease in levels of free-floating beta-amyloid, but only in the front part of the mouse brain. But could the treatment eliminate plaques? Yes.
The researchers repeated the experiment using a special mouse model of Alzheimer’s disease in which mice develop beta-amyloid plaques. Eight weeks of chronic treatment led to a significant decrease in the number of plaques in the prefrontal cortex of these mice.
The DREADD system is an incredible system for precise manipulation of specific neurons. But it is not very useful in human clinical settings. The latest experiments tested the effects of L-DOPA treatment. L-DOPA is a dopamine precursor molecule often used to treat Parkinson’s disease because it can enter the brain from the blood, where it is then converted to dopamine.
Treatment of model mice with L-DOPA resulted in increased neprilysin and decreased beta-amyloid plaques in the frontal and posterior parts of the brain. Model mice treated with L-DOPA for 3 months also performed better on memory tests than untreated model mice.
Tests have shown that neprilysin levels naturally decline with age in normal mice, particularly in the frontal part of the brain, possibly making it a good biomarker for preclinical or at-risk diagnoses of Alzheimer’s disease.
How dopamine causes the increase in neprilysin levels remains unknown and is the next research topic for Saido’s group.
“We have shown that L-DOPA treatment can help reduce harmful beta-amyloid plaques and improve memory function in a mouse model of Alzheimer’s disease,” said Watamura Naoto, first author of the study.
“L-DOPA treatment is known to have serious side effects in patients with Parkinson’s disease. Therefore, our next step is to study how dopamine regulates neprilysin in the brain, which should lead to a new preventive approach that could be implemented in the preclinical stage of Alzheimer’s disease.”
About this Alzheimer’s disease research news
Author: Adam Phillips
Source: RIKEN
Contact: Adam Phillips – RIKEN
Picture: Image credited to Neuroscience News
Original research: Access closed.
“The dopaminergic system promotes neprilysin-mediated amyloid-β degradation in the brain” by Takaomi Saido et al. Scientific signaling
Abstract
Dopaminergic system promotes neprilysin-mediated amyloid-β degradation in the brain
Amyloid-β (Aβ) deposition in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer’s disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also known as l-DOPA) induced Aβ degradation in the brain.
Chemogenetic approaches in mice revealed that activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aβ-degrading enzyme neprilysin and reduced the amount of Aβ deposition in the prefrontal cortex in a neprilysin-dependent manner.
Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice.
Treatment of AD model mice with levodopa reduced Aβ deposition and improved cognitive function.
These observations demonstrate that dopamine promotes brain region-specific, neprilysin-dependent degradation of Aβ, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.
