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


ABSTRACT: Longitudinal preclinical and clinical studies suggest that A? 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 A? 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 A?-induced injury. In neurons exposed to oligomeric A? in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit A?-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 A?-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.

SUBMITTER: Yang T 

PROVIDER: S-EPMC7683564 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Yang Tao T   Tran Kevin C KC   Zeng Anne Y AY   Massa Stephen M SM   Longo Frank M FM  

Scientific reports 20201123 1


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 (p75<sup>NTR</sup>) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75<sup>NTR</sup> will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect d  ...[more]

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