Reduction of mNAT1/hNAT2 Contributes to Cerebral Endothelial Necroptosis and Aβ Accumulation in Alzheimer’s Disease

Zou, Chengyu; Mifflin, Lauren; Hu, Zhirui; Zhang, Tian; Shan, Bing; Wang, Huibing; Xing, Xin; Zhu, Hong; Adiconis, Xian; Levin, Joshua Z.; Li, Fupeng; Liu, Chuan‐Fa; Yuan, Junying

doi:10.1016/j.celrep.2020.108447

Cited by 28 publications

(29 citation statements)

References 87 publications

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“…The ability of RIPK1 inhibition to block SARS-CoV-2 invasion to the CNS suggests that the virus-mediated RIPK1 activation may play an important role in breaking the blood-brain-barrier (BBB) which normally protects the CNS. We have recently reported the role of necroptosis in cerebromicrovascular endothelial cells mediated by RIPK1 and RIPK3 in promoting the BBB damage in Alzheimer’s disease 59 and in Nek1-deficient mice. 60 Future studies may be needed to directly investigate the role of necroptosis in mediating CNS invasion by SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation

Zhang

et al. 2021

Cell Res

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the ongoing global pandemic that poses substantial challenges to public health worldwide. A subset of COVID-19 patients experience systemic inflammatory response, known as cytokine storm, which may lead to death. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important mediator of inflammation and cell death. Here, we examined the interaction of RIPK1-mediated innate immunity with SARS-CoV-2 infection. We found evidence of RIPK1 activation in human COVID-19 lung pathological samples, and cultured human lung organoids and ACE2 transgenic mice infected by SARS-CoV-2. Inhibition of RIPK1 using multiple small-molecule inhibitors reduced the viral load of SARS-CoV-2 in human lung organoids. Furthermore, therapeutic dosing of the RIPK1 inhibitor Nec-1s reduced mortality and lung viral load, and blocked the CNS manifestation of SARS-CoV-2 in ACE2 transgenic mice. Mechanistically, we found that the RNA-dependent RNA polymerase of SARS-CoV-2, NSP12, a highly conserved central component of coronaviral replication and transcription machinery, promoted the activation of RIPK1. Furthermore, NSP12 323L variant, encoded by the SARS-CoV-2 C14408T variant first detected in Lombardy, Italy, that carries a Pro323Leu amino acid substitution in NSP12, showed increased ability to activate RIPK1. Inhibition of RIPK1 downregulated the transcriptional induction of proinflammatory cytokines and host factors including ACE2 and EGFR that promote viral entry into cells. Our results suggest that SARS-CoV-2 may have an unexpected and unusual ability to hijack the RIPK1-mediated host defense response to promote its own propagation and that inhibition of RIPK1 may provide a therapeutic option for the treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation

Zhang

et al. 2021

Cell Res

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“…Our study highlights the role of RIPK1 and necroptosis of cerebrovascular endothelial cells in mediating CNS pathology. We have shown that the necroptosis of cerebromicrovascular endothelial cells is involved in mediating BBB damage in Alzheimer's disease and ischemic stroke 51,61 . Here we show the role of RIPK1mediated necroptosis and apoptosis of cerebromicrovascular endothelial cells in BBB damage due to NEK1 deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…5e). Since the levels of acetyl-CoA, an important donor of acetyl-group, can regulate the acetylation of A20 protein and reduced acetylation of A20 protein ptomotes its lysosomal degradation 51 , we examined the levels of acetylated A20 in Nek1 Kat2J/Kat2J cells and whether ALCAR and sodium octanoate could upregulate A20. Consistent with the decreased acetyl-CoA levels, the acetylation of A20 protein was much lower in Nek1 Kat2J/Kat2J cells (Supplementary Fig.…”

Section: Nek1 Regulates Retromer Function By Phosphorylating Vps26bmentioning

confidence: 99%

NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation

Wang

Zou

et al. 2021

Nat Commun

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Loss-of-function mutations in NEK1 gene, which encodes a serine/threonine kinase, are involved in human developmental disorders and ALS. Here we show that NEK1 regulates retromer-mediated endosomal trafficking by phosphorylating VPS26B. NEK1 deficiency disrupts endosomal trafficking of plasma membrane proteins and cerebral proteome homeostasis to promote mitochondrial and lysosomal dysfunction and aggregation of α-synuclein. The metabolic and proteomic defects of NEK1 deficiency disrupts the integrity of blood–brain barrier (BBB) by promoting lysosomal degradation of A20, a key modulator of RIPK1, thus sensitizing cerebrovascular endothelial cells to RIPK1-dependent apoptosis and necroptosis. Genetic inactivation of RIPK1 or metabolic rescue with ketogenic diet can prevent postnatal lethality and BBB damage in NEK1 deficient mice. Inhibition of RIPK1 reduces neuroinflammation and aggregation of α-synuclein in the brains of NEK1 deficient mice. Our study identifies a molecular mechanism by which retromer trafficking and metabolism regulates cerebrovascular integrity, cerebral proteome homeostasis and RIPK1-mediated neuroinflammation.

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“…Due to its high specificity and efficiency, this vector allowed for repairing the BBB in incontinentia pigmenti disease, where a deficiency of the Nemo gene leads to a loss of brain ECs and a breakdown of the BBB (Dogbevia et al., 2017; Korbelin et al., 2016). Transduction of CNS ECs with the AAV‐BR1 vector could potentially be tuned to improve cerebral perfusion after a stroke (Park et al., 2021), impair vascularization of brain tumors, repair or otherwise modulate the BBB (Santisteban et al., 2020), and directly target the CNS through systemic blood circulation (epilepsy X. X. Liu et al., 2020; Alzheimer's Zou et al., 2020).…”

Section: Discussionmentioning

confidence: 99%

AAV‐BR1 targets endothelial cells in the retina to reveal their morphological diversity and to deliver Cx43

Ivanova

Corona

Eleftheriou

et al. 2021

J of Comparative Neurology

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Endothelial cells (ECs) are key players in the development and maintenance of the vascular tree, the establishment of the blood-brain barrier and control of blood flow. Disruption in ECs is an early and active component of vascular pathogenesis. However, our ability to selectively target ECs in the CNS for identification and manipulation is limited. Here, in the mouse retina, a tractable model of the CNS, we utilized a recently developed AAV-BR1 system to identify distinct classes of ECs along the vascular tree using a GFP reporter. We then developed an inducible EC-specific ectopic Connexin 43 (Cx43) expression system using AAV-BR1-CAG-DIO-Cx43-P2A-DsRed2 in combination with a mouse line carrying inducible CreERT2 in ECs. We targeted Cx43 because its loss has been implicated in microvascular impairment in numerous diseases such as diabetic retinopathy and vascular edema. GFP-labeled ECs were numerous, evenly distributed along the vascular tree and their morphology was polarized with respect to the direction of blood flow. After tamoxifen induction, ectopic Cx43 was specifically expressed in ECs. Similarly to endogenous Cx43, ectopic Cx43 was localized at the membrane contacts of ECs and it did not affect tight junction proteins. The ability to enhance gap junctions in ECs provides a precise and potentially powerful tool to treat microcirculation deficits, an early pathology in numerous diseases.

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Reduction of mNAT1/hNAT2 Contributes to Cerebral Endothelial Necroptosis and Aβ Accumulation in Alzheimer’s Disease

Abstract: Highlights d Cerebral venous ECs and capillary ECs in AD are vulnerable to necroptosis d Inhibition of endothelial cell necroptosis prevents BBB damage in AD mouse model d Insulin-resistance-mediated endothelial mNat1 reduction sensitizes EC necroptosis

Cited by 28 publications

References 87 publications

SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation

SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation

NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation

AAV‐BR1 targets endothelial cells in the retina to reveal their morphological diversity and to deliver Cx43

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