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Axxam SpA

Michela Stucchi, PhD | Lombardia, Italy

Axxam SpA

Michela Stucchi, PhD | Lombardia, Italy

Small Molecule P2X7 Antagonists for AD Treatment

(300 WORDS MAX.) Neuroinflammation, as characterized by activation of glia and elevated presence of inflammatory molecules, is a common component of the normal aging brain, yet is exacerbated in Alzheimer's disease and other neurodegenerative disorders. One of the characteristic pathological features of Alzheimer's disease is indeed a robust inflammatory response, involving microglia overactivation and release of pro-inflammatory signals, associated with extracellular deposition of amyloid-beta protein. Although assumed to be a local tissue response to combat the condition-specific pathology, neuroinflammation independently appears to actively contribute to CNS pathophysiology. Consideration of age-associated reactive gliosis in light of epidemiological studies reporting reduced risk of AD in patients with chronic use of anti-inflammatory drugs has stimulated intense research to investigate the implications of neuroinflammation leading to the identification of new promising molecular targets. The tight association between the P2X7 purinergic receptor and the key intracellular apparatus responsible for processing and release of the key pro-inflammatory cytokine IL-1β by microglia puts this molecular target at the very heart of CNS inflammation. In particular several studies have shown that P2X7R is an obligate participant in microglial activation caused by amyloid--beta. P2X7 antagonists can be useful in treating brain inflammation, and they may represent an innovative and relevant approach to treating AD and other neurodegenerative diseases involving microglia activation. The scope of project is the identification, through high-throughput screening, and early development, of bioactive molecules that limit microglia overactivation and neurotoxicity by specifically inhibiting the P2X7 receptor. These molecules will lay the ground for further development toward oral, selective drugs useful for treatment of Alzheimer's disease as well as of other neurodegenerative disorders.