Dopamine treatment can reduce Alzheimer’s plaques and improve memory

A new way to fight 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 treatment with dopamine could alleviate physical symptoms in the brain and improve memory. Published in the scientific journal Science signaling on August 6, 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. If similar results are found in human clinical trials, it could lead to a fundamentally new way to treat the disease.

The formation of hardened plaques around neurons is one of the first 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 peptide beta-amyloid that accumulate over time. In the new study, Saido’s team at RIKEN CBS focuses on the enzyme neprilysin, because previous experiments showed that genetic engineering that produces too much 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 this with drugs. Neprilysin pills or an injection are not feasible because it cannot enter the brain from the bloodstream. The first step in the new research was therefore a laborious screening of many molecules to determine 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 dish produced increased levels of neprilysin and decreased levels of free-floating beta-amyloid.

Now the serious experiments began. Using a DREADD system, they placed small designer receptors in the dopamine-producing neurons of the mouse’s ventral tegmental area. By adding a matching designer drug to the mice’s food, the researchers were able to continuously activate those neurons, and only those neurons, in the mouse brain. As in the dish, activation led to increased neprilysin and decreased levels of free-floating beta-amyloid, but only in the front part of the mouse brain. But can the treatment remove plaques? Yes. The researchers repeated the experiment with a special mouse model of Alzheimer’s disease, in which the mice develop beta-amyloid plaques. Eight weeks of chronic treatment resulted in significantly fewer 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 for human clinical environments. In the final experiments, the effects of the L-DOPA treatment were tested. 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 into dopamine. Treating the model mice with L-DOPA led to an increase in neprilysin and reduced beta-amyloid plaques in both 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 showed that neprilysin levels in normal mice declined naturally with age, especially in the front part of the brain, perhaps making it a good biomarker for preclinical or high-risk diagnoses of Alzheimer’s disease. How dopamine causes neprilysin levels to rise remains unknown and is the next research topic for Saido’s group.

We showed that treatment with L-DOPA can help reduce harmful beta-amyloid plaques and improve memory function in a mouse model of Alzheimer’s disease. But 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.”

Watamura Naoto, first author of the study