A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau

Pei, Lei; Wang, Shan; Jin, Huijuan; Bi, Lin-Lin; Wei, Na; Yan, Honglin; Yang, Xin; Yao, Chengye; Xu, Mengmeng; Shu, Shu; Guo, Yu; Yan, Haimeng; Wu, Jing; Li, Hao; Pang, Pei; Tian, Tian; Tian, Qing; Zhu, Ling‐Qiang; Shang, You; Lu, Youming

doi:10.1093/cercor/bhv096

Cited by 63 publications

(60 citation statements)

References 34 publications

(36 reference statements)

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“…3 days after the injection, ChR2 (the ΔG-rabies-DIO-ChR2 virus, ChATs ChR2+ mice) or NpHR (the ΔG-rabies-DIO-NpHR virus, ChATs NpHR+ mice) was expressed in the dNGIs pre-synaptic ChATs. We then prepared hippocampal slices (300 μm) from the ChATs ChR2+ mice or ChATs NpHR+ mice, as described before 26 , 46 , 55 , 57 . The slices were transferred to a holding chamber that contained artificial cerebrospinal fluid (ACSF, in mM: 124 NaCl, 3 KCl, 26 NaHCO 3 , 1.2 MgCl 2 •6H 2 O, 1.25 NaH 2 PO 4 •2H 2 O, 10 C 6 H 12 O 6 , and 2 CaCl 2 at pH 7.4, 305 mOsm) at 32 °C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses

et al. 2017

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Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) degenerate in the early stage of Alzheimer’s disease (AD). Here, we report that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice and regulate both the dNGIs survival and spatial pattern separation. In a mouse model that exhibits amyloid-β plaques similar to AD patients, cholinergic synaptic transmission, dNGI survival and spatial pattern separation are impaired. Activation of vChATs with theta burst stimulation (TBS) that alleviates the decay in cholinergic synaptic transmission effectively protects against spatial pattern separation impairments in the AD mice and this protection was completely abolished by inhibiting the dNGIs survival. Thus, the impairments of pattern separation-associated spatial memory in AD mice are in part caused by degeneration of cholinergic synaptic transmission that modulates the dNGIs survival.

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Section: Methodsmentioning

confidence: 99%

Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses

et al. 2017

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“…The borders of the infarct in each brain slice were outlined, and the area quantified using an ImageJ software. Infarct volume was calculated by integration of infarct areas for all slices of each brain (Arumugam et al, 2006; Tu et al, 2010; Pei et al, 2015). …”

Section: Methodsmentioning

confidence: 99%

Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation

Chen

Hatcher

et al. 2017

Front. Neurosci.

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Transient receptor potential canonical 6 (TRPC6) channels are permeable to Na+ and Ca2+ and are widely expressed in the brain. In this study, the role of TRPC6 was investigated following ischemia/reperfusion (I/R) and oxygen-glucose deprivation (OGD). We found that TRPC6 expression was increased in wild-type (WT) mice cortical neurons following I/R and in primary neurons with OGD, and that deletion of TRPC6 reduced the I/R-induced brain infarct in mice and the OGD- /neurotoxin-induced neuronal death. Using live-cell imaging to examine intracellular Ca2+ levels ([Ca2+]i), we found that OGD induced a significant higher increase in glutamate-evoked Ca2+ influx compared to untreated control and such an increase was reduced by TRPC6 deletion. Enhancement of TRPC6 expression using AdCMV-TRPC6-GFP infection in WT neurons increased [Ca2+]i in response to glutamate application compared to AdCMV-GFP control. Inhibition of N-methyl-d-aspartic acid receptor (NMDAR) with MK801 decreased TRPC6-dependent increase of [Ca2+]i in TRPC6 infected cells, indicating that such a Ca2+ influx was NMDAR dependent. Furthermore, TRPC6-dependent Ca2+ influx was blunted by blockade of Na+ entry in TRPC6 infected cells. Finally, OGD-enhanced Ca2+ influx was reduced, but not completely blocked, in the presence of voltage-dependent Na+ channel blocker tetrodotoxin (TTX) and dl-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) blocker CNQX. Altogether, we concluded that I/R-induced brain damage was, in part, due to upregulation of TRPC6 in cortical neurons. We postulate that overexpression of TRPC6 following I/R may induce neuronal death partially through TRPC6-dependent Na+ entry which activated NMDAR, thus leading to a damaging Ca2+ overload. These findings may provide a potential target for future intervention in stroke-induced brain damage.

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“…As the interaction of DAPK1-KD has been confirmed with the MT repeat binding domain 1 of tau (R1D) consisting of amino acids IGSTENLK, recently, a membrane-permeable peptide is generated by fusing the peptide IGSTENLK to the transduction domain of the HIV TAT protein, named TAT-R1D. Treatment with TAT-R1D (IGSTENLK) results in effective dissociation of DAPK1-tau complexes and significant decrease in the level of p S262 causes apparent alleviation of infraction area as well as the neurological deficits induced by cerebral ischemic stroke (Pei et al, 2015 ). Thus, blocking DAPK1-tau interaction could be a promising target for developing potential therapy for ischemic stroke.…”

Section: Targeting Dapk1 In Cancer and Neurodegenerative Diseasementioning

confidence: 99%

Death Associated Protein Kinase 1 (DAPK1): A Regulator of Apoptosis and Autophagy

Singh

Ravanan

Talwar

2016

Front. Mol. Neurosci.

157

141

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Death-Associated Protein Kinase 1 (DAPK1) belongs to a family of five serine/threonine (Ser/Thr) kinases that possess tumor suppressive function and also mediate a wide range of cellular processes, including apoptosis and autophagy. The loss and gain-of–function of DAPK1 is associated with various cancer and neurodegenerative diseases respectively. In recent years, mechanistic studies have broadened our knowledge of the molecular mechanisms involved in DAPK1-mediated autophagy/apoptosis. In the present review, we have discussed the structural information and various cellular functions of DAPK1 in a comprehensive manner.

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A Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau

Cited by 63 publications

References 34 publications

Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses

Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses

Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation

Death Associated Protein Kinase 1 (DAPK1): A Regulator of Apoptosis and Autophagy

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