The Riken Center team, headed by Dr. Takaomi Saido and using mice with Alzheimer’s, discovered that dopamine may lessen the brain’s physical symptoms and improve memory.
The study, featured in the August 6th issue of the Science Signaling journal, examines dopamine’s participation in producing the enzyme neprilysin that breaks down the brain’s damaging plaque. The next step is to test the treatment in clinical trials with human participants. If successful, it will bring about a new approach for the treatment of Alzheimer’s disease.
Closing In on Alzheimer’s
Hardening of the plaques surrounding neurons in the brain begin many years before memory loss and other behavioral symptoms are evident. Pieces of beta amyloid, a peptide, gradually accumulate forming plaques. The Riken team’s focus was on neprilysin as previous studies found that producing an overabundance of neprilysin (upregulation) caused a decrease in beta amyloid plaques. It also improved the memory of mice.
Manipulating mice may be a convenient way to produce neprilysin for experimental purposes, but medicine is required for people who have been diagnosed with Alzheimer’s. Neprilysin, in either injection or pill form, is not currently possible as it is unable to pass the blood-brain barrier. Relying on previous research, the team decided to concentrate on hormones generated by the hypothalamus that upregulate neprilysin in appropriate areas of the brain.
The researchers discovered that when they applied dopamine to the brain cells that had been cultured in a dish, there was an increase in neprilysin levels and levels of beta amyloid were reduced. Using a tool called DREADD, the researchers were able to remotely control behavior, neuronal activity and cellular signaling. DREADDS can be set in motion by certain designer drugs.
They added designer drugs to the animals’ food continuously activating selected neurons. In a manner similar to the results in the dish, neprilysin was increased and free-floating amyloid was decreased in one section of the brain. Then the team used a mouse model for Alzheimer’s disease that causes beta-amyloid to build up in the mice. Eight weeks of treatment resulted in a significant reduction of plaque in the prefrontal cortex.
Continued Success
Although the DREADD method works well for specific neurons, it lacks suitability for use in clinical settings involving humans. Therefore, experiments were conducted on L-DOPA’s effect. It is a molecule used in the treatment of Parkinson’s disease. L-DOPA crosses the blood-brain barrier where it becomes dopamine. These experiments involved treating mice with L-DOPA and led to increasing neprilysin while decreasing beta amyloid plaques in the brain’s frontal and posterior regions.
Additionally, L-DOPA was administered to the model mice for three months. The mice showed improved performance on memory tests compared to untreated mice. The tests were clear that neprilysin levels decreased naturally with age, especially in the brain’s frontal region. It would appear that this might be a satisfactory biomarker in preclinical disease prognoses.
The team is pressing on with the next step which is to determine how dopamine causes levels of neprilysin to increase. Yet along with its benefits, L-DOPA causes severe side effects in the treatment of Parkinson’s disease. Therefore, the next step is to identify how Dopamine can regulate neprilysin in the brain so that it can be used as a preventative approach during the initial stage of Alzheimer’s disease.
