Tissue-type plasminogen activator regulates p35-mediated Cdk5 activation in the postsynaptic terminal

Diaz, Ariel; Jeanneret, Valérie; Merino, Paola; McCann, Patrick; Yepes, Manuel

doi:10.1242/jcs.224196

Cited by 11 publications

(10 citation statements)

References 52 publications

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“…Accumulating evidence suggests that the activity of CDK5 is related to the expression of p35. [21][22][23] Compared with those in the sham-operated rats, CDK5 and p35 protein levels in the NP rats were greatly enhanced, which was consistent with the results of the immunofluorescence assay (Figure 2B and C) (all p < 0.01). At the same time, CEEB and CaMK II phosphorylation levels were obviously increased (Figure 2D) (both p < 0.01).…”

Section: Np Rats Have Increased Creb Phosphorylation Via the Cdk5/p35 Axissupporting

confidence: 84%

<p>Long Noncoding RNA H19 Induces Neuropathic Pain by Upregulating Cyclin-Dependent Kinase 5-Mediated Phosphorylation of cAMP Response Element Binding Protein</p>

Yuan

Ren

et al. 2020

JPR

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Objective Neuropathic pain (NP) is a debilitating condition caused by nervous system injury and chronic diseases. LncRNA H19 is upregulated in many human diseases, including NP. Cyclin-dependent kinase 5 (CDK5) aggressively worsens inflammatory action and nerve damage to cause severe NP. Phosphorylated cAMP response element binding protein (CREB) is detrimental to nerves and promotes NP progression. Herein, aim of our study was to assess the mechanism of lncRNA H19. Methods The NP rat model was established using chronic constriction injury (CCI). Paw withdrawal threshold (PWT) tests and paw withdrawal latency (PWL) tests were performed. Then, small interfering (si)RNA against H19 was intrathecally injected into rats to suppress H19 expression. Schwann cells were isolated from NP rats and transfected with siRNA-H19 or a lentivirus (LV)-based vector expressing H19. Inflammatory factors and glial fibrillary acidic protein (GFAP) were detected. Western blot analysis was conducted to detect CDK5/p35 and p-CREB expression. Finally, H19, CDK5 and CREB phosphorylation were tested with the combination of the CDK5 inhibitor roscovitine and transfection of LV-H19 and siRNA-H19. Finally, we investigated the binding relationships between H19 and miR-196a-5p and between miR-196a-5p and CDK5 and detected the mRNA expression of miR-196a-5p and CDK5 in rats with H19 knockdown and in Schwann cells with H19 knockdown. Results Highly expressed H19, CDK5/p-35 and p-CREB were observed in NP rats, accompanied by obviously decreased PWT and PWL, upregulated inflammatory factors and GFAP levels, and reduced 5-HT 2A and GABA B2 expression. siRNA-H19 restored NP-related indexes and downregulated CDK5/p35 and p-CREB phosphorylation. siRNA-H19, together with the CDK5 inhibitor roscovitine, reduced CDK5 and p-CREB expression in Schwann cells isolated from NP rats. Binding sites between H19 and miR-196a-5p and between miR-196a-5p and CDK5 were identified. Silencing H19 upregulated miR-196a-5p expression and downregulated CDK5 levels. Conclusion Our study demonstrated that silencing H19 inhibited NP by suppressing CDK5/p35 and p-CREB phosphorylation via the miR-196a-5p/CDK5 axis, which may provide new insight into NP treatment.

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Section: Np Rats Have Increased Creb Phosphorylation Via the Cdk5/p35 Axissupporting

confidence: 84%

<p>Long Noncoding RNA H19 Induces Neuropathic Pain by Upregulating Cyclin-Dependent Kinase 5-Mediated Phosphorylation of cAMP Response Element Binding Protein</p>

Yuan

Ren

et al. 2020

JPR

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“…Interference with Myo6 function, necessary for proper postsynaptic AMPA receptor trafficking, was shown to reduce synaptic numbers and impair AMPA receptor recruitment to postsynaptic sites (Wu et al, 2002;Osterweil et al, 2005;Nash et al, 2010). Likewise, a role for the stabilization of postsynaptic AMPA receptors has been assigned to Plat and the tPA-plasmin system (Diaz et al, 2019), the activity of which is decreased in aged individuals and existing models of AD (Ledesma et al, 2000;Melchor et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Interference With Complex IV as a Model of Age-Related Decline in Synaptic Connectivity

Kriebel

Ebel

Battke

et al. 2020

Front. Mol. Neurosci.

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Age-related impairment of mitochondrial function may negatively impact energydemanding processes such as synaptic transmission thereby triggering cognitive decline and processes of neurodegeneration. Here, we present a novel model for age-related mitochondrial impairment based on partial inhibition of cytochrome c oxidase subunit 4 (Cox4) of complex IV of the respiratory chain. miRNA-mediated knockdown of Cox4 correlated with a marked reduction in excitatory and inhibitory synaptic marker densities in vitro and in vivo as well as an impairment of neuronal network activity in primary neuronal cultures. Transcriptome analysis identified the deregulation of gene clusters, which link induced mitochondrial perturbation to impaired synaptic function and plasticity as well as processes of aging. In conclusion, the model of Cox4 deficiency reflects aspects of age-related dementia and might, therefore, serve as a novel test system for drug development.

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“…Tissue plasminogen activator (tPA) is a serine protease best known for its role in intravascular fibrinolysis, glutamate neurotransmission, and synaptic plasticity (Baranes et al, 1998;Benchenane et al, 2004;Samson and Medcalf, 2006;Diaz et al, 2019). In addition, tPA is required for the full expression of functional hyperemia (Park et al, 2008a;Iadecola, 2017;Anfray et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

et al. 2020

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The amyloid-b (Ab) peptide, a key pathogenic factor in Alzheimer's disease, attenuates the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a vital homeostatic response in which NMDA receptors (NMDARs) play a role through nitric oxide, and the CBF increase produced by endothelial factors. Tissue plasminogen activator (tPA), which is reduced in Alzheimer's disease and in mouse models of Ab accumulation, is required for the full expression of the NMDAR-dependent component of functional hyperemia. Therefore, we investigated whether tPA is involved in the neurovascular dysfunction of Ab. tPA activity was reduced, and the tPA inhibitor plasminogen inhibitor-1 (PAI-1) was increased in male mice expressing the Swedish mutation of the amyloid precursor protein (tg2576). Counteracting the tPA reduction with exogenous tPA or with pharmacological inhibition or genetic deletion of PAI-1 completely reversed the attenuation of the CBF increase evoked by whisker stimulation but did not ameliorate the response to the endothelium-dependent vasodilator acetylcholine. The tPA deficit attenuated functional hyperemia by suppressing NMDAR-dependent nitric oxide production during neural activity. Pharmacological inhibition of PAI-1 increased tPA activity, prevented neurovascular uncoupling, and ameliorated cognition in 11-to 12-month-old tg2576 mice, effects associated with a reduction of cerebral amyloid angiopathy but not amyloid plaques. The data unveil a selective role of the tPA in the suppression of functional hyperemia induced by Ab and in the mechanisms of cerebral amyloid angiopathy, and support the possibility that modulation of the PAI-1-tPA pathway may be beneficial in diseases associated with amyloid accumulation. Significance StatementAmyloid-b (Ab ) peptides have profound neurovascular effects that may contribute to cognitive impairment in Alzheimer's disease. We found that Ab attenuates the increases in blood flow evoked by neural activation through a reduction in tissue plasminogen activator (tPA) caused by upregulation of its endogenous inhibitor plasminogen inhibitor-1 (PAI-1). tPA deficiency prevents NMDA receptors from triggering nitric oxide production, thereby attenuating the flow increase evoked by neural activity. PAI-1 inhibition restores tPA activity, rescues neurovascular coupling, reduces amyloid deposition around blood vessels, and improves cognition in a mouse model of Ab accumulation. The findings demonstrate a previously unappreciated role of tPA in Ab -related neurovascular dysfunction and in vascular amyloid deposition. Restoration of tPA activity could be of therapeutic value in diseases associated with amyloid accumulation.

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Tissue-type plasminogen activator regulates p35-mediated Cdk5 activation in the postsynaptic terminal

Cited by 11 publications

References 52 publications

<p>Long Noncoding RNA H19 Induces Neuropathic Pain by Upregulating Cyclin-Dependent Kinase 5-Mediated Phosphorylation of cAMP Response Element Binding Protein</p>

<p>Long Noncoding RNA H19 Induces Neuropathic Pain by Upregulating Cyclin-Dependent Kinase 5-Mediated Phosphorylation of cAMP Response Element Binding Protein</p>

Interference With Complex IV as a Model of Age-Related Decline in Synaptic Connectivity

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

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