STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model

Abstract

Background: Abnormal tau accumulation in the brain has a positively correlation with neurodegeneration and memory deterioration, but the mechanism underlying tau-associated synaptic and cognitive impairments remains unclear. Our previous work has found that human full length tau (hTau) accumulation activated signal transducer and activator of transcription-1 (STAT1) to suppress N-methyl-D-aspartate receptors (NMDARs) expression, followed by memory deficits. STAT3 also belongs to STAT protein family and is reported to involve in regulation of synaptic plasticity and cognition. Here, we investigated the role of STAT3 in the cognitive deficits induced by hTau accumulation. Methods: In vitro studies HEK293 cells were used. EMSA, Luciferase reporter assay, and Immunoprecipitation were applied to detect STAT3 activity. In vivo studies, AAV virus were injected into the hippocampal CA3 region of C57 mice. Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence were applied to examine the level of synaptic proteins. Electrophysiological analysis, behavioral testing and Golgi impregnation were used to determine synaptic plasticity and memory ability recovery after overexpressing STAT3 or non-acetylated STAT1. Results: Our results showed that hTau accumulation acetylated STAT1 to retain STAT3 in the cytoplasm by increasing the binding of STAT1 with STAT3, and thus inactivated STAT3. Overexpressing STAT3 or non-acetylated STAT1 ameliorated hTau-induced synaptic loss and memory deficits by increasing the expression of NMDARs. Conclusions: Taken together, our study indicates that hTau accumulation impaired synaptic plasticity through STAT3 inactivation induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy

“…It has been extensively reported that tau accumulation induces neuron loss and synaptic impairments, which are closely related to cognitive deficits in AD ( Iqbal and Grundke-Iqbal, 2002 ; Giannakopoulos et al, 2003 ; Yin et al, 2016 ). We also found that overexpression of hTau or P301L hTau activated STAT1 and inactivated STAT3 to inhibit the expression of NMDARs, thus inducing dendritic plasticity deficits, including LTP suppression and spine density decrease, and memory deficits ( Li et al, 2019 ; Hong et al, 2020 ; Wan et al, 2021 ). In this study, PINK1 overexpression rescued neuron loss and synaptic damage, and ameliorated cognitive impairments by promoting the degradation of accumulated tau in the autophagy pathway, reducing tau accumulation in mitochondria and alleviating mitochondrial disorders.…”

“…We injected pAAV-SYN-human Tau-mCherry-3×FLAG-WPRE into the hippocampal CA1 region of mice for 1 month to mimic Alzheimer-like deposits of tau in the brain ( Andorfer et al, 2003 ; Lasagna-Reeves et al, 2011 ; Li et al, 2019 ; Wan et al, 2021 ). Meanwhile, pAAV-SYN-PINK1-EGFP-3×FLAG-WPRE was also co-injected to explore its effect on tau pathology.…”

“…RT-PCR was performed and analyzed using an ABI Step one plus Real-Time PCR System (Applied Biosystems). Primers for human TAU were F: 5′-CGC​CAG​GAG​TTC​GAA​GTG​AT-3′ and R: 5′-TCT​TGG​TGC​ATG​GTG​TAG​CC-3′ ( Korhonen et al, 2011 ) and primers for β-actin were F: 5′- CAA​ATG​TTG​CTT​GTC​TGG​TG-3′ and R: 5′-GTC​AGT​CGA​GTG​CAC​AGT​TT-3′ ( Wan et al, 2021 ).…”

HSPB8 Overexpression Ameliorates Cognitive Impairment in Diabetic Mice via Inhibiting NLRP3 Inflammation Activation

“…According to the previous report [ 16 ], a novel object recognition test was performed in a box (50 × 50 × 50 cm). First, mouse was put in the box to adapt to the environment for 5 min in an empty box 24 h before testing.…”

Mechanisms Involved in Microglial-Interceded Alzheimer’s Disease and Nanocarrier-Based Treatment Approaches

“…JAK/STAT and NF-kB are two critical pathways involved in the pathogenesis of AD and neuroinflammation. Studies have shown their correlation with microglial activation, and hence, these pathways offer a target for inhibiting microglial activation [58]. α-asarone and tanshinone-I are two naturally occurring bioactive compounds involved in the modulation of the NF-kB pathway and inactivation of microglia (inhibition of M1 polarization) [59].…”