Dopamine loss and neuroinflammation in AD: two sides of the same coin?

Project objectives

In this project we aim to demonstrate that chronic brain inflammation in Alzheimer's disease is a consequence of alterations in the midbrain dopaminergic system. Neuroinflammation - or chronic inflammation of the brain - is a typical hallmark of Alzheimer's disease (AD), driven by the uncontrolled activation of the brain's microglia. These immune cells fight the disease effectively in the early stages, but their chronic activation later becomes detrimental. How the transition from protective early to harmful late microglia occurs is unclear, but factors that inhibit it offer neuroprotection. Here, we want to demonstrate that the neurotransmitter dopamine has a neuroprotective role, demonstrating that neuroinflammation is due to decreased dopamine levels in the AD brain. In fact, dopamine is essential for many brain functions, such as memory and reward.  Using the Tg2576 mouse model of AD, we demonstrated that dopaminergic neurons in the midbrain degenerate very early, causing progressive dopamine loss in AD-relevant brain areas. Dopamine reduction is related to memory and reward impairments, which can be ameliorated by treatment with dopaminergic drugs. We and others have also demonstrated that dopamine deficits are present in patients, as early as the stage of mild cognitive impairment (MCI), suggesting that addressing early dysfunction of the dopaminergic system may hold promise for new drug treatments. This project aims to demonstrate a link between the degeneration of dopaminergic neurons and neuroinflammation, and whether a treatment with a dopaminergic drug (levodopa) in AD animals can have an anti-inflammatory effect.

Start and end date

February 2021 - January 2024

Project Manager

Prof. Marcello D'Amelio, Coordinator

Coordinating institution of the project

Università Campus Bio-Medico di Roma

Other Institutions involved

IRCCS Santa Lucia Foundation, Rome

Funding source

Alzheimer's Association (USA)

Economic value of the project

$ 150.000