Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS1 transgenic mice

Unger, Michael S.; Schernthaner, P.; Marschallinger, Julia; Mrowetz, Heike; Aigner, Ludwig

doi:10.1186/s12974-018-1304-4

Cited by 101 publications

(102 citation statements)

References 98 publications

(126 reference statements)

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“…In the same manner, PLX5622 increased viral load and enhanced mortality in a number of murine models of viral infection (32)(33)(34). A similar protective role of microglia was also apparent in the progression of neurodegeneration in APP-PS1 transgenic mice (35), the extent of excitotoxic injury in a model of brain injury induced by cerebral ischemia (36) and the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP)(37).…”

Section: Discussionmentioning

confidence: 68%

“…However, experiments carried out with PLX5622 and PLX3397 revealed no sex differences in the extent of microglia depletion induced by either of these treatments (31,35,(54)(55)(56)(57). In the same manner, female and male Cx3cr1-Dtr rats were found to respond identically to diphtheria toxin administration in terms of microglia depletion and body weight loss (15).…”

Section: Discussionmentioning

confidence: 84%

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Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats

Vichaya

Malik

Sominsky

et al. 2020

Preprint

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Background: Production of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation.Methods: Depletion of microglia was achieved in C57BL/6 mice by chronic oral administration of PLX5622, a specific antagonist of colony stimulating factor-1 receptor, and in rats by a knock-in model in which the diphtheria toxin receptor was expressed under the control of the endogenous fractalkine receptor (CX3CR1) promoter sequence. After successful microglia depletion, mice and rats were injected with a sickness-inducing dose of lipopolysaccharide according to a 2 (depletion versus control) x 2 (LPS versus saline) factorial design. Sickness was measured by body weight loss and decreased locomotor activity in rats and mice, and reduced voluntary wheel running in mice. Results: Chronic administration of PLX5622 in mice and administration of diphtheria toxin to knock-in rats depleted microglia and peripheral tissue macrophages. However, it did not abrogate the inducible expression of proinflammatory cytokines in the brain in response to LPS and even exacerbated it for some of the cytokines. In accordance with these neuroimmune effects, LPS-induced sickness was not abrogated, rather it was exacerbated when measured by running wheel activity in mice. Conclusions: These findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 84%

Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats

Vichaya

Malik

Sominsky

et al. 2020

Preprint

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“…Noteworthy, an immunomodulatory effect of MSC‐EVs on macrophages has been described by Agudelo et al 96 Along with microglia and macrophages, a certain amount of other cells derived from blood can contribute to the inflammatory response that characterizes the AD brains. In fact, neutrophils, T cells, and B cells could cross the damaged blood brain barrier (see, eg, Reference 97), thus contributing to the exacerbation of central inflammation. Indeed, activation of circulating peripheral immune cells is observed in patients with early stages of AD 98‐100 .…”

Section: Discussionmentioning

confidence: 99%

Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease

Losurdo

Pedrazzoli

D'Agostino

et al. 2020

Stem Cells Translational Medicine

168

132

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The critical role of neuroinflammation in favoring and accelerating the pathogenic process in Alzheimer's disease (AD) increased the need to target the cerebral innate immune cells as a potential therapeutic strategy to slow down the disease progression. In this scenario, mesenchymal stem cells (MSCs) have risen considerable interest thanks to their immunomodulatory properties, which have been largely ascribed to the release of extracellular vesicles (EVs), namely exosomes and microvesicles. Indeed, the beneficial effects of MSC‐EVs in regulating the inflammatory response have been reported in different AD mouse models, upon chronic intravenous or intracerebroventricular administration. In this study, we use the triple‐transgenic 3xTg mice showing for the first time that the intranasal route of administration of EVs, derived from cytokine‐preconditioned MSCs, was able to induce immunomodulatory and neuroprotective effects in AD. MSC‐EVs reached the brain, where they dampened the activation of microglia cells and increased dendritic spine density. MSC‐EVs polarized in vitro murine primary microglia toward an anti‐inflammatory phenotype suggesting that the neuroprotective effects observed in transgenic mice could result from a positive modulation of the inflammatory status. The possibility to administer MSC‐EVs through a noninvasive route and the demonstration of their anti‐inflammatory efficacy might accelerate the chance of a translational exploitation of MSC‐EVs in AD.

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“…For example, Dagher et al (2015) showed a positive effect on cognitive behaviors using the PLX5622 diet in 15-month-old 3xTg-AD mice, but with no effect on plaque burden or plaque size. Subsequently, Unger et al (2018) reported that in 12-month-old APP-PS1 transgenic mice that also have significant levels of amyloid burden and fed with PLX5622 diet, there was neither an impact on plaque burden, nor cognition. The differences in behavioral outcomes reported in the two mouse models could easily be explained by contrasting experimental protocols in each study, and influences of housing conditions, animal gender, and age and feeding (Gemma and Bachstetter, 2013).…”

Section: Discussionmentioning

confidence: 99%

Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion

Ortega-Martínez¹,

Palla²,

Zhang³

et al. 2019

J. Neurosci.

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that presently affects an estimated 5.7 million Americans. Understanding the basis for this disease is key for the development of a future successful treatment. In this effort, we previously reported that mouse prion protein-promoter-driven, ubiquitous expression of familial AD (FAD)-linked human PSEN1 variants in transgenic mice impairs environmental enrichment (EE)-induced proliferation and neurogenesis of adult hippocampal neural progenitor cells (AHN-PCs) and in a non-cell autonomous manner. These findings were confirmed in PS1 M146V/؉ mice that harbor an FAD-linked mutation in the endogenous PSEN1 gene. We now demonstrate that CSF1R antagonist-mediated microglial depletion in transgenic male mice expressing mutant presenilin 1 (PS1) or PS1 M146V/؉ "knock-in" mice leads to a complete rescue of deficits in proliferation, differentiation and survival of AHNPCs. Moreover, microglia depletion suppressed the heightened baseline anxiety behavior observed in transgenic mice expressing mutant PS1 and PS1 M146V/؉ mice to levels observed in mice expressing wild-type human PS1 or nontransgenic mice, respectively. These findings demonstrate that in mice expressing FAD-linked PS1, microglia play a critical role in the regulation of EE-dependent AHNPC proliferation and neurogenesis and the modulation of affective behaviors.

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Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS1 transgenic mice

Cited by 101 publications

References 98 publications

Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats

Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats

Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease

Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion

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