The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain.

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. Editor's summary: The accumulation of amyloid-β in the brain is associated with progressive cognitive impairment in Alzheimer's disease. Watamura et al. found that a treatment commonly used to treat a symptom of Parkinson's disease also induced the breakdown of amyloid-β. In mice, dopamine release in the brain increased the abundance and activity of the enzyme neprilysin, which degraded amyloid-β specifically in the working memory center of the brain. Levodopa induced these effects and improved cognitive function in aged and Alzheimer's disease model mice, suggesting that the approach might be explored for patients with Alzheimer's disease. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]