Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

Iulita, M. Florencia; Vallerand, Diane; Beauvillier, Mélissa; Haupert, Nathalie; Ulysse, Corinne A.; Gagné, Audrey; Vernoux, Nathalie; Duchemin, Sonia; Boily, Michaël; Tremblay, Marie‐Ève; Girouard, Hélène

doi:10.1186/s12974-018-1090-z

Cited by 32 publications

(24 citation statements)

References 53 publications

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“…Microglial cell bodies and processes were further compared between plaque-associated, neuronal dystrophy associated, and ultrastructurally healthy tissue of APP Swe -PS1Δe9 mice using a non-parametric Kruskal-Wallis test without matching, followed by Dunn’s multiple comparisons post-hoc test. Data are expressed as mean ± standard error of the mean (SEM) [56, 57]. The sample size ( n ) refers to individual microglial cell bodies or processes as previously performed for quantitative ultrastructural analyses [56, 58–60].…”

Section: Methodsmentioning

confidence: 99%

Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology

Hajj

Savage

Bisht

et al. 2019

J Neuroinflammation

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118

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Background Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid β (fΑβ) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, Aβ drives a robust and prolonged inflammatory response via its recognition by microglia, the brain’s immune cells. Microglial reactivity to fAβ plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cognitive decline in AD. Methods In the current study, we performed correlative light, transmission, and scanning electron microscopy to provide insights into microglial structural and functional heterogeneity. We analyzed microglial cell bodies and processes in areas containing fAβ plaques and neuronal dystrophy, dystrophy only, or appearing healthy, among the hippocampus CA1 of 14-month-old APP Swe -PS1Δe9 mice versus wild-type littermates. Results Our quantitative analysis revealed that microglial cell bodies in the AD model mice were larger and displayed ultrastructural signs of cellular stress, especially nearby plaques. Microglial cell bodies and processes were overall less phagocytic in AD model mice. However, they contained increased fibrillar materials and non-empty inclusions proximal to plaques. Microglial cell bodies and processes in AD model mice also displayed reduced association with extracellular space pockets that contained debris. In addition, microglial processes in healthy subregions of AD model mice encircled synaptic elements more often compared with plaque-associated processes. These observations in mice were qualitatively replicated in post-mortem hippocampal samples from two patients with AD (Braak stage 5). Conclusion Together, our findings identify at the ultrastructural level distinct microglial transformations common to mouse and human in association with amyloid pathology.

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Section: Methodsmentioning

confidence: 99%

Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology

Hajj

Savage

Bisht

et al. 2019

J Neuroinflammation

Self Cite

118

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“…These data are underscored by findings from in vitro studies where LPS‐induced microglial activation decreased transendothelial electrical resistance of an endothelial monolayer by disrupting tight junction proteins, including cldn5 (Sumi, Nishioku, Takata, Matsumoto & Watanabe, 2010). Interestingly, blood pressure and angiotensin II, a peptide hormone involved in the development of hypertension, have been shown to contribute to hippocampal microglia activation in mice (Iulita, Vallerand, Beauvillier, Haupert & Ulysse, 2018).…”

Section: Vascular Function In Depression and Resilience To Stressmentioning

confidence: 99%

Neurobiology of resilience in depression: immune and vascular insights from human and animal studies

Dudek

Dion‐Albert

Kaufmann

et al. 2019

Eur J of Neuroscience

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“…In addition, although our study was designed to investigate the critical role played by microglia in the context of hypertension-induced cognitive dysfunction, we cannot exclude the possible contribution of other glial cells in the BBB dysfunction and cognitive impairment induced by Ang II. In particular, the activation of astrocytes has been evidenced in another study with Ang II hypertensive mice 71 . Of note, the inhibition of CSF1R using PLX5622 has been shown to not alter the number of astrocytes nor oligodendrocytes 36 .…”

Section: Discussionmentioning

confidence: 91%

Pharmacological depletion of microglia and perivascular macrophages prevents vascular Cognitive Impairment in Ang II-induced Hypertension

Kerkhofs¹,

Hagen²,

Milanova³

et al. 2020

Theranostics

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Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1 gfp/wt x Thy1 yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages. Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia /PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

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Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

Cited by 32 publications

References 53 publications

Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology

Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology

Neurobiology of resilience in depression: immune and vascular insights from human and animal studies

Pharmacological depletion of microglia and perivascular macrophages prevents vascular Cognitive Impairment in Ang II-induced Hypertension

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