P75 neurotrophin receptor as a therapeutic target for drug development to treat neurological diseases

Abstract

The interaction of neurotrophins with their receptors is involved in the pathogenesis and progression of various neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and acute and chronic cerebral damage. The p75 neurotrophin receptor (p75NTR) plays a pivotal role in the development of neurological dysfunctions as a result of its high expression, abnormal processing and signalling. Therefore, p75NTR represents as a vital therapeutic target for the treatment of neurodegeneration, neuropsychiatric disorders and cerebrovascular insufficiency. This review summarizes the current research progress on the p75NTR signalling in neurological deficits. We also summarize the present therapeutic approaches by genetically and pharmacologically targeting p75NTR for the attenuation of pathological changes. Based on the evolving knowledge, the role of p75NTR in the regulation of tau hyperphosphorylation, Aβ metabolism, the degeneration of motor neurons and dopaminergic neurons has been discussed. Its position as a biomarker to evaluate the severity of diseases and as a druggable target for drug development has also been elucidated. Several prototype small molecule compounds were introduced to be crucial in neuronal survival and functional recovery via targeting p75NTR. These small molecule compounds represent desirable agents in attenuating neurodegeneration and cell death as they abolish activation‐induced neurotoxicity of neurotrophins via modulating p75NTR signalling. More comprehensive and in‐depth investigations on p75NTR‐based drug development are required to shed light on effective treatment of numerous neurological disorders.

The potential role of the p75 receptor in schizophrenia: neuroimmunomodulation and making life or death decisions

“…One possibility is that small molecule ligands such as LMA11A-type compounds, which block proneurotrophin binding to p75, may have utility in minimising potential neuronal damage during the neuroinflammatory state in schizophrenia ( Xiong et al, 2022 ). In support of this, small molecule ligands targeting the p75 receptor have high central nervous system bioavailability and show neuroprotective and anti-inflammatory effects in animal models of infection, neurodegeneration and injury, by specifically activating pro-survival pathways of p75 signalling ( Xie et al, 2021 ; Nasoohi et al, 2023 ).…”

DAPT improves behavioral abnormalities and rescues the hippocampal Oligodendrocyte precursor cell differentiation in cuprizone-induceddemyelination mouse model

“…Neurotrophin receptor P75 (P75NTR) is a low a nity receptor in cell membrane, which can bind all known members of the trophin family and other corresponding ligands [4]. P75NTR is also a typical transmembrane protein composed of segmented domains [5].…”