In vivo functions of p75NTR: challenges and opportunities for an emerging therapeutic target

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 42; no. 9; pp. 772 - 788
• Main Authors: Malik, Subash C., Sozmen, Elif G., Baeza-Raja, Bernat, Le Moan, Natacha, Akassoglou, Katerina, Schachtrup, Christian
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.09.2021
• Subjects: Alzheimer’s disease; fibrinolysis; neurodegenerative diseases; neurotrophin receptors; small molecule inhibitors; fibrinolysis; small molecule inhibitors; neurodegenerative diseases; Alzheimer’s disease; neurotrophin receptors
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2021.06.006

The p75 neurotrophin receptor (p75NTR) functions at the molecular nexus of cell death, survival, and differentiation. In addition to its contribution to neurodegenerative diseases and nervous system injuries, recent studies have revealed unanticipated roles of p75NTR in liver repair, fibrinolysis, lung fibrosis, muscle regeneration, and metabolism. Linking these various p75NTR functions more precisely to specific mechanisms marks p75NTR as an emerging candidate for therapeutic intervention in a wide range of disorders. Indeed, small molecule inhibitors of p75NTR binding to neurotrophins have shown efficacy in models of Alzheimer’s disease (AD) and neurodegeneration. Here, we outline recent advances in understanding p75NTR pleiotropic functions in vivo, and propose an integrated view of p75NTR and its challenges and opportunities as a pharmacological target. p75NTR is a driver of disease pathogenesis in neurological, metabolic, and fibrotic diseases.p75NTR is highly pleiotropic interacting with multiple ligands, co-receptors, and signaling molecules.Blockade of p75NTR binding to its ligands or intracellular partners has therapeutic potential.Tissue-specific selective targeting of p75NTR may avoid potentially adverse on-target effects.