Using dopamine as a treatment, researchers have discovered a promising approach to treating Alzheimer’s disease. The treatment in mice increased the brain’s neprilysin enzyme activity and reduced damaging Alzheimer ’s-linked amyloid-beta plaques. This discovery offers hope for new treatments if the results can be replicated in human trials, which is the next phase of the study.
Amyloid-β (Aβ) protein deposition in the brain is a key factor in the development of Alzheimer’s disease (AD). The formation of hardened plaques around neurons is one of the earliest signs of Alzheimer’s disease, often beginning decades before behavioral symptoms such as memory loss are detected. These plaques are formed from pieces of the amyloid-beta peptide (Aβ) that accumulate over time.
Recent studies suggest that dopamine, a neurotransmitter essential for brain function, may play a role in reducing these Aβ deposits.
A new way to combat Alzheimer’s disease has been discovered by Takaomi Saido and his team at the RIKEN Center for Brain Science (CBS) in Japan. Using mice with the disease, the researchers found that treating them with dopamine could alleviate physical symptoms in the brain, as well as improve memory.
Published in the journal Science Signaling, the study examines the role of dopamine in promoting the production of neprilysin, an enzyme that can break down the harmful plaques in the brain that are the hallmark of Alzheimer’s disease.
In the new study, the team focused on this enzyme because previous experiments have shown that genetic manipulation that produces excess neprilysin in the brain, a process called upregulation, resulted in fewer beta-amyloid plaques and improved memory in mice.
While genetically engineering mice to produce neprilysin is useful experimentally, to treat people with the disease, we need a way to do it using drugs. Neprilysin pills or injections are not viable because they cannot enter the brain through the bloodstream.
The first step in the new study was therefore a tedious screening of many molecules to determine which ones might naturally regulate 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 dish produced increased levels of neprilysin and reduced levels of free-floating beta-amyloid.
Now the serious experiments began. Using a DREADD system, they inserted tiny designer receptors into the dopamine-producing neurons of the mouse ventral tegmental area. The DREADD system is an amazing system for precisely manipulating specific neurons. But it’s not very useful in human clinical settings.
By adding a matching designer drug to the mice’s food, the researchers were able to continuously activate these neurons, and only these neurons, in the mice’s brains. Just as in the dish, the activation led to increased neprilysin and decreased levels of free-floating amyloid beta, but only in the front of the mice’s brains. But could the treatment remove the plaques? Yes.
The researchers repeated the experiment using a special mouse model of Alzheimer’s disease in which the mice developed amyloid beta plaques. Eight weeks of chronic treatment resulted in significantly fewer plaques in the prefrontal cortex of these mice, a region of the brain important for cognitive functions such as decision-making and memory.
The final 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.
Treating the model mice with L-DOPA led to increased neprilysin and decreased beta-amyloid plaques in the front and back of the brain. Model mice treated with L-DOPA for 3 months also performed better on memory tests than untreated model mice.
The tests showed that neprilysin levels naturally decreased with age in normal mice, particularly in the front of the brain, perhaps making it a good biomarker for preclinical diagnostics or for at-risk Alzheimer’s disease.
How dopamine causes neprilysin levels to increase 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,” explains Watamura Naoto, first author of the study.
“However, L-DOPA treatment is known to have serious side effects in patients with Parkinson’s disease. Therefore, our next step is to investigate how dopamine regulates neprilysin in the brain, which should provide a new preventive approach that can be initiated in the preclinical stage of Alzheimer’s disease.”
These results suggest that dopamine plays an important role in the clearance of Aβ protein and that therapies that increase dopamine in the brain, such as levodopa, may be a promising strategy to treat this part of the pathology of Alzheimer’s disease. If similar results are found in human clinical trials, it could lead to a fundamentally new way of treating the disease.
In summary, this study opens up new possibilities for treatments for Alzheimer’s disease by exploring the role of dopamine in the degradation of toxic proteins associated with the disease. This may help to slow or even improve cognitive decline in patients.
READ MORE:
The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain
Watamura et al.
SCIENCE SIGNALING. 6 Aug 2024. Vol 17, Issue 848.
DOI: 10.1126/scisignal.adk1822
Abstract:
Deposition of amyloid-β (Aβ) 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 called l-DOPA) induced Aβ degradation in the brain. Chemogenetic approaches in mice revealed that the 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 deposits 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. Treating 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.
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