Engineering microglia to treat Alzheimer’s disease

Objetivo

"Microglia, the resident immune cells of the brain, are increasingly implicated in Alzheimer’s disease (AD) pathogenesis by genetic studies and functional evidence showing defective recognition and clearance of amyloid-beta (Aβ) peptides. Inefficient microglial clearance of Aβ plaques leads to progressive accumulation, enhanced neuroinflammation, and neuronal loss. While current antibody therapies target Aβ, these interventions face significant safety concerns, limiting pharmacology. This ERC Proof of Concept proposal seeks to build on partial successes of anti-Aβ immunotherapy and introduces an innovative strategy that targets the amyloid cascade and cellular phase hypotheses of AD. I propose engineering transplantable human microglia with enhanced and selective ability to clear Aβ aggregates. Leveraging concepts from CAR-T cell therapy, these microglia will be equipped to express synthetic receptors, allowing precise temporal and spatial control of their therapeutic function. Recent advances in cell therapy for neurodegeneration highlight microglia’s potential as ""living drugs,"" capable of sustained and specific activity in the brain, representing a paradigm shift akin to oncological cell therapies. If successful, this ERC PoC will deliver the first proof-of-concept for engineered CAR-microglia as a therapeutic strategy for Alzheimer’s disease and generate the key preclinical data required to support patent protection and the creation of a microglia-based cell therapy platform for clinical translation. "