The mechanism described in experiments conducted on experimental models associates the combined loss of dopamine and serotonin with the activation of inflammatory processesThese events trigger hyperphosphorylation of the tau protein and accelerate the deposition of amyloid plaques, resulting in a worsening of the cognitive symptoms typical of the disease. This is what emerges from the Italian study, coordinated by teacher. Marcellus D'Amelio, Professor of Physiology at theUniversità Campus Bio-Medico di Roma and director of the Laboratory of Molecular Neurosciences of the Santa Lucia IRCCS of Rome, in collaboration with theCatholic University of the Sacred Heart, la "A. Gemelli" University Hospital Foundation IRCCS, il Department of Translational Research ofUniversity of Pisa and theIRCCS Neuromed of Pozzilli, which was published on October 13 on Molecular neurodegeneration*.
Research has shown that damage to specific midbrain nuclei responsible for producing dopamine (Ventral Tegmental Area and Substantia Nigra) and serotonin (Interpeduncular Nucleus) triggers powerful neuroinflammation processes in the hippocampus, one of the brain areas most affected in Alzheimer's, whose degeneration leads to memory loss, a clinical sign of the disease.
From a therapeutic perspective, researchers have observed that, in experimental models, increasing dopamine or serotonin levels significantly reduces neuroinflammation and tau protein hyperphosphorylation. This evidence, of great translational importance, paves the way for precision medicine strategies aimed at slowing the progression of Alzheimer's disease in patients with midbrain vulnerability.
“This study adds to previous findings from our team and contributes to understanding the role of degeneration of the Ventral Tegmental Area and other midbrain areas in Alzheimer's disease. - explains the professor D'Amelio - This study clarifies why patients with a reduction in the volume of this important area and its related anatomical and functional brain circuitry experience a more rapid progression from physiological aging to cognitive decline. Restoring the balance of the dopaminergic and serotonergic systems could therefore represent a new therapeutic approach to help slow the progression of the disease.. In the last few years - continues - MRI and brain connectivity studies conducted on patients have indicated that the midbrain is involved early in the Alzheimer's continuum. With this work, we show how its degeneration can fuel inflammation and tau-related processes in the hippocampus. It's not a cure, but it provides additional insight into a stage where intervention could make a difference.
The results of this research not only shed new light on the pathogenic mechanisms of Alzheimer's, but They also open up study perspectives applicable to other neurodegenerative diseases, in which the dopaminergic and serotonergic systems play a key role, like other forms of dementia and Parkinson's diseaseThis integrated approach could contribute to the development of more targeted diagnostic and therapeutic strategies in the future, fostering progress towards precision neuroscience at the service of patients.
Alzheimer's disease affects approximately 1,2 million people in Italy and is the leading cause of dementia. Over 150.000 new cases are diagnosed each year, with a significant impact on families: more than 80% of daily care falls to family members and caregivers who cope with the disease alongside the patient..
*Published in Molecular Neurodegeneration - DOI: 10.1186/s13024-025-00893-2 -
Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer's Disease
