IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior

Chakrabarty, Paramita; Li, Andrew; Ceballos‐Diaz, Carolina; Eddy, James A.; Funk, Cory C.; Moore, Brenda D.; DiNunno, Nadia; Rosario, Awilda M.; Cruz, Pedro; Verbeeck, Christophe; Sacino, Amanda N.; Nix, Sarah; Janus, Christopher; Price, Nathan D.; Das, Pritam; Golde, Todd E.

doi:10.1016/j.neuron.2014.11.020

Cited by 309 publications

(300 citation statements)

References 75 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.

327

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.

327

326

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“…It was only in the CC group that there was an inverse correlation between the CSF IL-10 concentrations and spontaneously reported pain intensity and discomfort (Table 3). Based on our current data, we hypothesize that IL-10 may directly modulate the painful experience by modulating the inflammatory response or by a recently identified immunoproteostasis mechanism (Chakrabarty et al, 2015).…”

Section: Discussionmentioning

confidence: 69%

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

Lerman

Davis

Bertram

et al. 2016

Psychoneuroendocrinology

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a b s t r a c tObjective: Although posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1␤), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF␣) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC). Methods: After completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30 min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110 min post capsaicin injection. Inflammatory (IL-1␤, IL-6, IL-8 TNF␣) and antiinflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110 min. Results: Following intramuscular capsaicin injection, pro-inflammatory cytokines [TNF␣, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL-1␤ significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10 min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70 min post injection. Conclusion: These findings show significant central nervous system (CNS) differences in the inflammatory response to a deep pain stimulus in combat veterans with and without PTSD. They support the concept that abnormally elevated neuroinflammatory response to pain stimuli may be one CNS mechanism accounting for the high co-occurrence of PTSD and pain.Published by Elsevier Ltd.

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“…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%

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.

344

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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IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior

Cited by 309 publications

References 75 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

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

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

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