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Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model.

ABSTRACT: p75 neurotrophin receptor (p75NTR) has been implicated in Alzheimer's disease (AD). However, whether p75NTR is involved in Tau hyperphosphorylation, one of the pathologies observed in AD, remains unclear. In our previous study, the extracellular domain of p75NTR blocked amyloid beta (Aβ) toxicity and attenuated Aβ-induced Tau hyperphosphorylation. Here we show that, in the absence of Aβ, p75NTR regulates Tau phosphorylation in the transgenic mice with the P301L human Tau mutation (pR5). The knockout of p75NTR in pR5 mice attenuated the phosphorylation of human Tau. In addition, the elevated activity of kinases responsible for Tau phosphorylation including glycogen synthase kinase 3 beta; cyclin-dependent-kinase 5; and Rho-associated protein kinase was also inhibited when p75NTR is knocked out in pR5 mice at 9 months of age. The increased caspase-3 activity observed in pR5 mice was also abolished in the absence of p75NTR. Our study also showed that p75NTR is required for Aβ- and pro-brain derived neurotrophin factor (proBDNF)-induced Tau phosphorylation, in vitro. Overall, our data indicate that p75NTR is required for Tau phosphorylation, a key event in the formation of neurofibrillary tangles, another hallmark of AD. Thus, targeting p75NTR could reduce or prevent the pathologic hyperphosphorylation of Tau.

SUBMITTER: Manucat-Tan NB

PROVIDER: S-EPMC6756909 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model.

Mañucat-Tan Noralyn B NB Shen Lin-Lin LL Bobrovskaya Larisa L Al-Hawwas Mohammed M Zhou Fiona H FH Wang Yan-Jiang YJ Zhou Xin-Fu XF

Aging 20190903 17

p75 neurotrophin receptor (p75NTR) has been implicated in Alzheimer's disease (AD). However, whether p75NTR is involved in Tau hyperphosphorylation, one of the pathologies observed in AD, remains unclear. In our previous study, the extracellular domain of p75NTR blocked amyloid beta (Aβ) toxicity and attenuated Aβ-induced Tau hyperphosphorylation. Here we show that, in the absence of Aβ, p75NTR regulates Tau phosphorylation in the transgenic mice with ...[more]

PMID: 31479419

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Project description:BackgroundStreptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Previous studies suggest that p75NTR signaling influences cell survival, apoptosis, and proliferation in brain-injured conditions. However, the role of p75NTR signaling in regulating pneumococcal meningitis (PM)-induced neuroinflammation and altered neurogenesis remains largely to be elucidated.Methodsp75NTR signaling activation in the pathological process of PM was assessed. During acute PM, a small-molecule p75NTR modulator LM11A-31 or vehicle was intranasally administered for 3 days prior to S. pneumoniae exposure. At 24 h post-infection, clinical severity, histopathology, astrocytes/microglia activation, neuronal apoptosis and necrosis, inflammation-related transcription factors and proinflammatory cytokines/mediators were evaluated. Additionally, p75NTR was knocked down by the adenovirus-mediated short-hairpin RNA (shRNA) to ascertain the role of p75NTR in PM. During long-term PM, the intranasal administration of LM11A-31 or vehicle was continued for 7 days after successfully establishing the PM model. Dynamic changes in inflammation and hippocampal neurogenesis were assessed.ResultsOur results revealed that both 24 h (acute) and 7, 14, 28 day (long-term) groups of infected rats showed increased p75NTR expression in the brain. During acute PM, modulation of p75NTR through pretreatment of PM model with LM11A-31 significantly alleviated S. pneumoniae-induced clinical severity, histopathological injury and the activation of astrocytes and microglia. LM11A-31 pretreatment also significantly ameliorated neuronal apoptosis and necrosis. Moreover, we found that blocking p75NTR with LM11A-31 decreased the expression of inflammation-related transcription factors (NF-κBp65, C/EBPβ) and proinflammatory cytokines/mediators (IL-1β, TNF-α, IL-6 and iNOS). Furthermore, p75NTR knockdown induced significant changes in histopathology and inflammation-related transcription factors expression. Importantly, long-term LM11A-31 treatment accelerated the resolution of PM-induced inflammation and significantly improved hippocampal neurogenesis.ConclusionOur findings suggest that the p75NTR signaling plays an essential role in the pathogenesis of PM. Targeting p75NTR has beneficial effects on PM rats by alleviating neuroinflammation and promoting hippocampal neurogenesis. Thus, the p75NTR signaling may be a potential therapeutic target to improve the outcome of PM.

Dataset Information

Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model.

Publications

Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model.

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