Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies

Abstract Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linke...

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Autores principales:	Tao Yang, Kevin C. Tran, Anne Y. Zeng, Stephen M. Massa, Frank M. Longo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8348a7a6f53749899f4b1ee9d564946e
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spelling	oai:doaj.org-article:8348a7a6f53749899f4b1ee9d564946e2021-12-02T11:42:13ZSmall molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies10.1038/s41598-020-77210-y2045-2322https://doaj.org/article/8348a7a6f53749899f4b1ee9d564946e2020-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-77210-yhttps://doaj.org/toc/2045-2322Abstract Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.Tao YangKevin C. TranAnne Y. ZengStephen M. MassaFrank M. LongoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-17 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tao Yang Kevin C. Tran Anne Y. Zeng Stephen M. Massa Frank M. Longo Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
description	Abstract Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.
format	article
author	Tao Yang Kevin C. Tran Anne Y. Zeng Stephen M. Massa Frank M. Longo
author_facet	Tao Yang Kevin C. Tran Anne Y. Zeng Stephen M. Massa Frank M. Longo
author_sort	Tao Yang
title	Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
title_short	Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
title_full	Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
title_fullStr	Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
title_full_unstemmed	Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
title_sort	small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/8348a7a6f53749899f4b1ee9d564946e
work_keys_str_mv	AT taoyang smallmoleculemodulationofthep75neurotrophinreceptorinhibitsmultipleamyloidbetainducedtaupathologies AT kevinctran smallmoleculemodulationofthep75neurotrophinreceptorinhibitsmultipleamyloidbetainducedtaupathologies AT anneyzeng smallmoleculemodulationofthep75neurotrophinreceptorinhibitsmultipleamyloidbetainducedtaupathologies AT stephenmmassa smallmoleculemodulationofthep75neurotrophinreceptorinhibitsmultipleamyloidbetainducedtaupathologies AT frankmlongo smallmoleculemodulationofthep75neurotrophinreceptorinhibitsmultipleamyloidbetainducedtaupathologies
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Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies

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