Interleukin-10 Production in Response to Amyloid-β Differs between Slow and Fast Decliners in Patients with Alzheimer’s Disease

Asselineau, Delphine; Benlhassan, Khadija; Arosio, Beatrice; Mari, Daniela; Ferri, Evelyn; Casati, Martina; Gussago, Cristina; Tedone, Enzo; Annoni, Giorgio; Mazzola, Paolo; Piette, F.; Belmin, Joël; Pariel, Sylvie; Bornand, Anne; Beaudeux, Jean Louis; Doulazmi, Mohamed; Mariani, Jean; Bray, Dorothy

doi:10.3233/jad-142832

Cited by 26 publications

(18 citation statements)

References 42 publications

(65 reference statements)

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“…Importantly, serum IL-10 levels are affected in individuals with AD (Asselineau et al, 2015;Remarque et al, 2001;Swardfager et al, 2010). In peripheral blood mononuclear cells, IL-10 synthesis is almost ceased in fast cognitive decliners, whereas its level is slightly increased in slow cognitive decliners with AD (Asselineau et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Chronic Amyloid β Oligomer Infusion Evokes Sustained Inflammation and Microglial Changes in the Rat Hippocampus via NLRP3

et al. 2019

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Microglia are instrumental for recognition and elimination of amyloid β oligomers (AβOs), but the long-term consequences of AβO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AβO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AβO or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. AβO infusion evoked a sustained inflammatory response including activation of NF-κB, triggered microglia activation and increased the expression of pattern recognition and phagocytic receptors. Aβ plaques were not detectable likely due to microglial elimination of infused oligomers. In addition, we found upregulation of neuronal inhibitory ligands and their cognate microglial receptors, while downregulation of Esr1 and Scn1a, encoding estrogen receptor alpha and voltage-gated sodium-channel Na(v)1.1, respectively, was observed. These changes were associated with impaired hippocampus-dependent spatial memory and resembled early neurological changes seen in Alzheimer's disease. To investigate the role of inflammatory actions in memory deterioration, we performed MCC950 infusion, which specifically blocks the NLRP3 inflammasome. MCC950 attenuated AβO-evoked microglia reactivity, restored expression of neuronal inhibitory ligands, reversed downregulation of ERα, and abolished memory impairments. Furthermore, MCC950 abrogated AβO-invoked reduction of serum IL-10. These findings provide evidence that in response to AβO infusion microglia change their phenotype, but the resulting inflammatory changes are sustained for at least one month after the end of AβO challenge. Lasting NLRP3-driven inflammatory alterations and altered hippocampal gene expression contribute to spatial memory decline.

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Section: Discussionmentioning

confidence: 99%

Chronic Amyloid β Oligomer Infusion Evokes Sustained Inflammation and Microglial Changes in the Rat Hippocampus via NLRP3

et al. 2019

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“…The association of interleukin-10 polymorphisms with risk of Alzheimer's disease was recently reported (79). It was also reported that IL-10 production in response to amyloid-␤ differs between AD patients with slow and fast progression of cognitive decline, based on the observation that A␤-stimulated peripheral blood mononuclear cells from slow decliners present higher IL-10 levels compared with controls, whereas in fast decliners, IL-10 production was abolished (80). These findings suggest that the increase in IL-10 levels found in MSC/neuronal cocultures may represent an important component of the neuroprotective action of MSCs, by neutralizing the cytotoxic inflammatory process induced by A␤Os and down-regulating the synthesis of pro-inflammatory cytokines, as proposed previously (81).…”

Section: Neuroprotective Potential Of Mscs In Alzheimer's Diseasementioning

confidence: 92%

Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers

Godoy

Saraiva²,

Carvalho

et al. 2018

Journal of Biological Chemistry

160

127

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Alzheimer's disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. Soluble oligomers of the amyloid-β peptide (AβOs) are thought to be proximal neurotoxins involved in early neuronal oxidative stress and synapse damage, ultimately leading to neurodegeneration and memory impairment in AD. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AβOs on hippocampal neurons. To this end, we established transwell cocultures of rat hippocampal neurons and MSCs. We show that MSCs and MSC-derived extracellular vesicles protect neurons against AβO-induced oxidative stress and synapse damage, revealed by loss of pre- and postsynaptic markers. Protection by MSCs entails three complementary mechanisms: 1) internalization and degradation of AβOs; 2) release of extracellular vesicles containing active catalase; and 3) selective secretion of interleukin-6, interleukin-10, and vascular endothelial growth factor to the medium. Results support the notion that MSCs may represent a promising alternative for cell-based therapies in AD.

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“…It is primarily produced by T cells and natural killer cells but can also be secreted by microglia and astrocytes (Fultz et al, 1993). IFN-γ is upregulated in the AD brain (Huberman et al, 1994) and a polymorphism is associated with fast progressing AD, suggesting it could play a detrimental role in the course of AD (Asselineau et al, 2015).…”

Section: Il-1βmentioning

confidence: 99%

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

Frost

Jonas

2019

Front. Aging Neurosci.

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Alzheimer's disease (AD) is marked by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), neuronal death and synaptic loss, and inflammation in the brain. AD research has, in large part, been dedicated to the understanding of Aβ and NFT deposition as well as to the pharmacological reduction of these hallmarks. However, recent GWAS data indicates neuroinflammation plays a critical role in AD development, thereby redirecting research efforts toward unveiling the complexities of AD-associated neuroinflammation. It is clear that the innate immune system is intimately associated with AD progression, however, the specific roles of glia and neuroinflammation in AD pathology remain to be described. Moreover, inflammatory processes have largely been painted as detrimental to AD pathology, when in fact, many immune mechanisms such as phagocytosis aid in the reduction of AD pathologies. In this review, we aim to outline the delicate balance between the beneficial and detrimental aspects of immune activation in AD as a more thorough understanding of these processes is critical to development of effective therapeutics for AD.

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Interleukin-10 Production in Response to Amyloid-β Differs between Slow and Fast Decliners in Patients with Alzheimer’s Disease

Cited by 26 publications

References 42 publications

Chronic Amyloid β Oligomer Infusion Evokes Sustained Inflammation and Microglial Changes in the Rat Hippocampus via NLRP3

Chronic Amyloid β Oligomer Infusion Evokes Sustained Inflammation and Microglial Changes in the Rat Hippocampus via NLRP3

Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

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