Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

Guillot-Sestier, Marie-Victoire; Doty, Kevin R.; Gate, David; Rodríguez, Javier; Leung, Brian P.; Rezai‐Zadeh, Kavon; Town, Terrence

doi:10.1016/j.neuron.2014.12.068

Cited by 314 publications

(308 citation statements)

References 79 publications

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“…However, although microglia can phagocytose and digest aggregated Aβ in a lysosome-dependent manner (22,62,63), our data indicate that they contributed only a small part to the steady-state pool of PGRN and lysosomes around amyloid plaques. Our results do not rule out physiologically important roles for microglia and their lysosomes in β-amyloid metabolism, as proposed by recent studies (64)(65)(66). However, we establish that the majority of the PGRN that accumulates at amyloid plaques is axonal.…”

Section: Discussioncontrasting

confidence: 84%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

316

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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Section: Discussioncontrasting

confidence: 84%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

316

326

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“…Aβ plaques were quantified using the Surfaces function followed by volume analysis in IMARIS software (Bitplane). IMARIS-based quantification of microglial number, morphology, and Aβ phagocytosis followed previously described methods using the Colocalization and Surfaces functions (28)(29)(30)33). To calculate Aβ internalization ratio, the volume of Aβ within CD68 + phagolysosomes was normalized to microglia number and total Aβ volume within the field.…”

Section: Methodsmentioning

confidence: 99%

“…3K). In addition to traditional proinflammatory cytokines, two recent studies demonstrated that the antiinflammatory cytokine interleukin 10 (IL-10) negatively regulates amyloid pathology (27,28). We therefore also examined levels of IL-10 in all four groups.…”

Section: Microglial Activation and Phagocytosis Is Altered In Rag-5xfadmentioning

confidence: 99%

“…We therefore used high-power confocal z-stack imaging with IMARIS software colocalization, surface reconstruction, and volumetric quantification to analyze Aβ phagocytosis (28)(29)(30). Using this approach, we quantified the proportion of Aβ localized to microglial phagolysosomes and detected a nearly 39.6% decrease in phagocytic efficiency (P = 0.016) in Rag-5xfAD microglia vs. WT-5xfAD microglia (Fig.…”

Section: Microglial Activation and Phagocytosis Is Altered In Rag-5xfadmentioning

confidence: 99%

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The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

334

287

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The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptiveinnate immunity cross talk and accelerated disease progression.is the leading cause of age-related neurodegeneration, affecting over 5.2 million people in the United States alone (1). Pathologically, AD is characterized by two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, that are accompanied by neuroinflammation, including microgliosis, elevated cytokine production, and activation of complement pathways (2-5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. 6-8). However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10). Although much of the data implicating microglia in AD has come from neuropathological investigation, recent genome-wide association studies have provided the first genetic evidence (to our knowledge) linking microglia dysfunction to AD, with the discovery of risk polymorphisms in several immune system genes: CR1, TREM2, CD33, HLA-DRB5, MS4A6A, and ABCA7 (8,(11)(12)(13)(14)(15).In contrast to the field's increasing understanding of the role of innate immunity in AD, comparatively little is known about whether the adaptive immune system might also influence AD. Those studies that have examined these peripheral populations have largely focused on questions about their potential as biomarkers or their role in active Aβ immunization (3, 16). However, the adaptive and innate immune systems rarely fu...

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“…However, the outcomes have been mixed for other preclinical models. In differing mouse models of Alzheimer's disease, viral mediated overexpression of IL-10 worsens amyloid-β plaque deposition, while IL-10 deficiency promotes amyloid-β plaque clearance and improved outcomes on cognitive tasks (Chakrabarty et al, 2015;Guillot-Sestier et al, 2015). In contrast, intracerebroventricular infusions of IL-10 receptor blocking antibodies exacerbates disease onset in the SOD1 G93A model of ALS, while targeted intrathecal overexpression of IL-10 in CD11b-expressing microglial cells greatly improves disease progression (Gravel et al, 2016).…”

Section: Future Research Directions and Clinical Implicationsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

218

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

Cited by 314 publications

References 79 publications

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

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