Hyperphosphorylation of tau protein in the ipsilateral thalamus after focal cortical infarction in rats

Dong, Dawei; Zhang, Yusheng; Yang, Wanyong; Wangqin, Runqi; Xu, Anding; Ruan, Yiwen

doi:10.1016/j.brainres.2013.11.004

Cited by 22 publications

(14 citation statements)

References 29 publications

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“…Tau hyperphosphorylation has been observed in rat ischemic cortex after MCAO (Wen et al 2004a(Wen et al ,b, 2007, as well as in the gerbil hippocampus after global ischemia (Morioka et al 2006), which suggests that tau hyperphosphorylation may contribute to ischemic neuronal injury. Recently, hyperphosphorylated tau (Thr231 and Ser199) and secondary neuronal death were observed in the ipsilateral thalamus remote from the primary ischemic region after MCAO (Dong et al 2014). Together, these findings indicate that accumulation of hyperphosphorylated tau may also contribute to MCAO-induced secondary damage in remote areas.…”

Section: Discussionmentioning

confidence: 83%

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Overactivation of NR2B‐containing NMDA receptors through entorhinal–hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion

Liu

Chen

et al. 2015

Journal of Neurochemistry

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Middle cerebral artery occlusion (MCAO) induces secondary damages in the hippocampus that is remote from primary ischemic regions. Tau hyperphosphorylation is an important risk for neurodegenerative diseases. Increased tau phosphorylation has been identified in ischemic cortex, but little is known regarding the changes in the hippocampus. We showed that unilateral transient MCAO induced accumulation of hyperphosphorylated tau and concurrent dephosphorylation of glycogen synthase kinase-3b at Ser 9 in the ipsilateral hippocampus. These MCAO-induced changes were not reproduced when glutamatergic inputs from the entorhinal cortex to the hippocampus were transected; however, the changes were mimicked by intrahippocampal N-methyl-D-aspartate (NMDA) administration. Inhibition of NMDA receptor (NMDAR) subunit NR2B, but not NR2A activity in the hippocampus attenuated the accumulation of hyperphosphorylated tau and spatial cognitive impairment in MCAO rats. Together, our data suggest that overactivation of NR2B-containing NMDARs through entorhinal-hippocampal connection plays an important role in the accumulation of hyperphosphorylated tau in the hippocampus following MCAO. Glycogen synthase kinase-3b is an important protein kinase involved in NMDARs-mediated tau hyperphosphorylation. This study indicates that early inhibition of NR2B-containing NMDARs may represent a potential strategy to prevent or delay the occurrence of post-stroke dementia.

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Section: Discussionmentioning

confidence: 83%

“…Recently, hyperphosphorylated tau (Thr231 and Ser199) and secondary neuronal death were observed in the ipsilateral thalamus remote from the primary ischemic region after MCAO (Dong et al . ). Together, these findings indicate that accumulation of hyperphosphorylated tau may also contribute to MCAO‐induced secondary damage in remote areas.…”

Section: Discussionmentioning

confidence: 97%

Overactivation of NR2B‐containing NMDA receptors through entorhinal–hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion

Liu

Chen

et al. 2015

Journal of Neurochemistry

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“…Tau and Aβ proteins are characteristic pathological features in neurodegenerative diseases such as Alzheimer's diseases (56). Interestingly, recent studies also link these proteins with secondary thalamic injury after stroke (52,57). Phosphorylated tau proteins are increased in VPM neurons at Day 7 and Day 28 after cortical ischemic stroke in rats (52).…”

Section: Tau and Aβ Accumulationmentioning

confidence: 99%

“…Interestingly, recent studies also link these proteins with secondary thalamic injury after stroke (52,57). Phosphorylated tau proteins are increased in VPM neurons at Day 7 and Day 28 after cortical ischemic stroke in rats (52). The majority of the phosphorylated tau-positive neurons are also TUNELpositive, suggesting that the hyperphosphorylated tau may be responsible for the secondary thalamic injury through apoptotic pathways (52).…”

Section: Tau and Aβ Accumulationmentioning

confidence: 99%

“…A few studies have reported apoptosis in the ipsilesional thalamus after focal cortical ischemic stroke. In rat MCAO model, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells is increased in the ipsilateral VPM at Day 7 and 28 after stroke (52,53). Following the same timeline, mitochondrial transmembrane depolarization is detected with elevated ratio of cleaved caspase-3/caspase-3 and cleaved caspase-9/caspase-9, indicating increased caspase activation and apoptosis in the ipsilesional thalamus post-stroke (53).…”

Section: Apoptosismentioning

confidence: 99%

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Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

et al. 2020

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Stroke is one of the major causes of chronic disability worldwide and increasing efforts have focused on studying brain repair and recovery after stroke. Following stroke, the primary injury site can disrupt functional connections in nearby and remotely connected brain regions, resulting in the development of secondary injuries that may impede long-term functional recovery. In particular, secondary degenerative injury occurs in the connected ipsilesional thalamus following a cortical stroke. Although secondary thalamic injury was first described decades ago, the underlying mechanisms still remain unclear. We performed a systematic literature review using the NCBI PubMed database for studies that focused on the secondary thalamic degeneration after cortical ischemic stroke. In this review, we discussed emerging studies that characterized the pathological changes in the secondary degenerative thalamus after stroke; these included excitotoxicity, apoptosis, amyloid beta protein accumulation, blood-brain-barrier breakdown, and inflammatory responses. In particular, we highlighted key findings of the dynamic inflammatory responses in the secondary thalamic injury and discussed the involvement of several cell types in this process. We also discussed studies that investigated the effects of blocking secondary thalamic injury on inflammatory responses and stroke outcome. Targeting secondary injuries after stroke may alleviate network-wide deficits, and ultimately promote stroke recovery.

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VX-765 Alleviates β-Amyloid Deposition and Secondary Degeneration in the Ipsilateral Hippocampus and Ameliorates Cognitive Decline after Focal Cortical Infarction in Rats

et al. 2022

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Focal cortical infarction leads to secondary degeneration of the ipsilateral hippocampus, which is associated with poststroke cognitive impairment. VX-765 is a potent small-molecule caspase-1 inhibitor that protects against central nervous system diseases. The present study aimed to determine the protective effects of VX-765 on β-amyloid (Aβ) deposition and secondary degeneration in the hippocampus as well as cognitive decline after cortical infarction. Sprague–Dawley rats were used to establish a distal middle cerebral artery occlusion (dMCAO) model and randomly divided into the vehicle and VX-765 groups. Rats in the vehicle and VX-765 groups, respectively, were subcutaneously injected with VX-765 (50 mg/kg/d) and an isopycnic vehicle once a day for 28 days, starting 1 h after dMCAO. At the end of this 28-day period, cognitive impairment was evaluated with the Morris water maze, and secondary hippocampal damage was evaluated with Nissl staining and immunostaining methods. Neuronal damage and pyroptosis were detected by TUNEL and immunoblotting. The results revealed that VX-765 treatment ameliorated poststroke cognitive dysfunction after ischemia. VX-765 reduced Aβ deposition, neuronal loss, and glial activation compared with the vehicle control. In addition, VX-765 treatment increased BDNF levels and normalized synaptophysin protein levels in the hippocampus after cortical infarction. Notably, VX-765 treatment significantly reduced the expression of the pyroptosis-related molecules caspase-1, NLRP3, apoptosis-associated speck-like protein (ASC), gasdermin D, IL-1β, and IL-18. Additionally, VX-765 significantly decreased the numbers of TUNEL-positive cells and the levels of Bax and cleaved caspase-3 (cC3) and enhanced the levels of Bcl-2 and Bcl-xl after ischemia. Inflammatory pathways, such as the NF-κB and mitogen-activated protein kinase (MAPK) pathways, were inhibited by VX-765 treatment after ischemia. These findings revealed that VX-765 reduced Aβ deposition, pyroptosis, and apoptosis in the ipsilateral hippocampus, which may be associated with reduced secondary degeneration and cognitive decline following focal cortical infarction.

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Hyperphosphorylation of tau protein in the ipsilateral thalamus after focal cortical infarction in rats

Cited by 22 publications

References 29 publications

Overactivation of NR2B‐containing NMDA receptors through entorhinal–hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion

Overactivation of NR2B‐containing NMDA receptors through entorhinal–hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

VX-765 Alleviates β-Amyloid Deposition and Secondary Degeneration in the Ipsilateral Hippocampus and Ameliorates Cognitive Decline after Focal Cortical Infarction in Rats

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