Concurrent cell type–specific isolation and profiling of mouse brains in inflammation and Alzheimer’s disease

Swartzlander, Dan B.; Propson, Nicholas E.; Roy, Ethan; Saito, Takashi; Saido, Takaomi C.; Wang, Baiping; Zheng, Hui

doi:10.1172/jci.insight.121109

Cited by 44 publications

(40 citation statements)

References 58 publications

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“…To confirm astrocytic genome editing, we analyzed cleavage of the Lcn2 genome in SDH astrocytes isolated by means of cell sorting with anti-astrocyte cell-surface antigen 2 (ACSA-2). 23 In addition to the band for the uncleaved Lcn2 gene (Fig 4, D, arrow), we identified 2 bands at lower base pairs in SDH astrocytes obtained from mice expressing SaCas9 and sgLcn2 (Fig 4, D, arrowheads), indicating that the genome of astrocytic Lcn2 had been edited. We observed no cleaved band for the astrocytic Lcn2 gene in mice without sgLcn2 (Fig 4, D, and see Fig E5 in this article's Online Repository at www.jacionline.org).…”

Section: Sensitization Of Grp-grpr Signaling Under Chronic Itch Condimentioning

confidence: 80%

Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

Koga

Yamagata

Kohno

et al. 2020

Journal of Allergy and Clinical Immunology

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Section: Sensitization Of Grp-grpr Signaling Under Chronic Itch Condimentioning

confidence: 80%

Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

Koga

Yamagata

Kohno

et al. 2020

Journal of Allergy and Clinical Immunology

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“…To assess the cell type expression of sEH, we used a flow cytometry-based concurrent brain cell type acquisition (CoBrA) method to simultaneously isolate astrocytes, microglia and vascular endothelial cells (29). qPCR analysis of Ephx2 revealed that sEH is highly expressed in sorted astrocytes where its levels are significantly elevated compared to N-Tg controls ( Fig.…”

Section: Tppu Blocks Astroglial Seh Upregulation and Lps-induced Inflmentioning

confidence: 99%

Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

Ghosh

Comerota

Wan

et al. 2020

Preprint

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AbstractNeuroinflammation has been increasingly recognized to play critical roles in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide hydrolase (sEH). We found that sEH is predominantly expressed in astrocytes where its levels are significantly elevated in postmortem human AD brains and in β-amyloid mouse models, and the latter is correlated with drastic reductions of brain EpFA levels. Using a highly potent and specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report here that TPPU treatment potently protected against LPS-induced inflammation in vitro and in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation, and this is associated with reduced β–amyloid pathology and improved synaptic integrity and cognitive function. Importantly, TPPU treatment reinstated and positively correlated EpFA levels in the 5xFAD mouse brain, demonstrating its brain penetration and target engagement. These findings support TPPU as a novel therapeutic target for the treatment of AD and related disorders.One Sentence SummaryWe show that soluble epoxide hydrolase is upregulated in AD patients and mouse models, and that inhibition of this lipid metabolic pathway using an orally bioavailable small molecule inhibitor is effective in restoring brain epoxy fatty acids, ameliorating AD neuropathology and improving synaptic and cognitive function.

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“…Alterations in EC function could then propagate to other NGVU cells, activating astrocytes and microglia. In support of this, a paper developing a concurrent cell-type specific isolation method [52], reported gene expression changes (upregulation of pro-inflammatory cytokines, chemokines, cell adhesion molecules, including ICAM1)…”

Section: Discussionmentioning

confidence: 88%

Acute effects of systemic inflammation upon the neuro-glial-vascular unit and cerebrovascular function.

Brezzo

Simpson

Ameen‐Ali

et al. 2019

Preprint

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Background Brain health relies on a tightly regulated system known as neurovascular function whereby the cellular constituents of the neuro-glial-vascular unit (NGVU) regulate cerebral haemodynamics in accordance with neuronal metabolic demand. Disruption of neurovascular function impairs brain health and is associated with the development of disease, including Alzheimer’s disease. The NGVU is also a key site of action for neuroinflammatory responses and contributes to the transition of systemic inflammation to neuroinflammatory processes. Thus, systemic inflammatory challenges may cause a shift in NGVU operation towards neuroimmune over neurovascular actions, leading to altered neurovascular function. Methods To investigate this, rats were injected with lipopolysaccharide (LPS) (2mg/kg) to induce a systemic inflammatory response, or vehicle, and brain haemodynamic responses to sensory and non-sensory (hypercapnia) stimuli were assessed in vivo using optical imaging techniques. Following imaging, animals were perfused and their brains extracted to histologically characterise components of the NGVU to determine the association between altered underlying pathology and in vivo blood flow regulation. Results LPS-treated animals showed altered haemodynamic function and cerebrovascular dynamics six hours after LPS administration. Histological assessment identified a significant increase in astrogliosis, microgliosis and endothelial activation in LPS-treated animals. Conclusions Our data shows that an acutely induced systemic inflammatory response is able to rapidly alter in-vivo haemodynamic function and is associated with significant changes in the cellular constituents of the NGVU. We suggest that these effects are initially mediated by endothelial cells, which are directly exposed to the circulating inflammatory stimulus and have been implicated in regulating functional hyperaemia.

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Concurrent cell type–specific isolation and profiling of mouse brains in inflammation and Alzheimer’s disease

Cited by 44 publications

References 58 publications

Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

Acute effects of systemic inflammation upon the neuro-glial-vascular unit and cerebrovascular function.

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