Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia

Kim, Changyoun; Ho, Dong Hwan; Suk, Ji Eun; You, Sungyong; Michael, Sarah; Kang, Junghee; Lee, Sung Joong; Masliah, Eliezer; Hwang, Daehee; Lee, He Jin; Lee, Seung-Jae

doi:10.1038/ncomms2534

Cited by 698 publications

(741 citation statements)

References 57 publications

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“…We found that activation of TLR2 serves as a critical trigger for hIAPP-induced Il1b expression in both BMDMs and cultured islets. Interestingly, diverse amyloidogenic peptides appear to act as endogenous ligands for TLR2: activation of TLR1/2 has been described for A␤ (32,33), serum amyloid A (34), lysozyme fibrils (12), curli fibrils (11), and ␣-synuclein (35). Lysozyme may also activate TLR2/6 (12), and our data suggest that heterodimerization with TLR6 is required for sensing of IAPP by TLR2.…”

Section: Discussionmentioning

confidence: 92%

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Westwell‐Roper¹,

Denroche

Ehses

et al. 2016

Journal of Biological Chemistry

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Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. Like other amyloidogenic peptides, human IAPP induces macrophage IL-1␤ secretion by stimulating both the synthesis and processing of proIL-1␤, a pro-inflammatory cytokine that (when chronically elevated) impairs beta cell insulin secretion. We sought to determine the specific mechanism of IAPP-induced proIL-1␤ synthesis. Soluble IAPP species produced early during IAPP aggregation provided a Toll-like-receptor-2-(TLR2-) dependent stimulus for NF-B activation in HEK 293 cells and bone marrow-derived macrophages (BMDMs). Nonamyloidogenic rodent IAPP and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and its downstream adaptor protein MyD88 were required for IAPP-induced cytokine production by BMDMs, a process that is partially dependent on autoinduction by IL-1. BMDMs treated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1␤ secretion, whereas late IAPP aggregates induced NLRP3-dependent IL-1␤ secretion by LPS-primed macrophages. Moreover, inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These data suggest participation by both soluble and fibrillar aggregates in IAPPinduced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction.

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Section: Discussionmentioning

confidence: 92%

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Westwell‐Roper¹,

Denroche

Ehses

et al. 2016

Journal of Biological Chemistry

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“…IM injection of human Δ71-82 αS was used to test the hypothesis that induction of αS pathology occurs through amyloidogenic conformational templating. LPS was used as a control for potential inflammatory effects induced by αS (38)(39)(40). Forty to 90 d post IM injection (dpi) with hfib21-140 or mfib αS, M83 +/+ Tg mice developed a unilateral foot drop that progressed rapidly to a bilateral foot drop followed by full hind limb paralysis within a week of onset ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Sacino¹,

Brooks²,

Thomas³

et al. 2014

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

293

343

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It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.amyloid | Parkinson disease S ynucleinopathies are a group of diseases defined by the presence of amyloidogenic α-synuclein (αS) inclusions that can occur in neurons and glia of the central nervous system (CNS) (1-4). In Parkinson disease (PD), a causative role for αS has been established via the discovery of mutations in the αS gene SNCA resulting in autosomal-dominant PD (4-11). Although αS inclusions (e.g., Lewy bodies) are the hallmark pathology of PD, how they contribute to disease pathogenesis remains controversial (1,3,4,12).Postmortem studies have suggested that αS pathology may spread following neuroanatomical tracts (13-15) and between cells (16-18). αS pathology has also been found in the peripheral nervous system (PNS): for example, in the enteric and pelvic plexus (19,20). And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21-26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27, 28). A caveat of the direct intracerebral injection of αS is tha...

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“…119 On further examination, it was discovered that extracellular -synuclein released from neuronal cells serves as an endogenous agonist for Toll-like receptor 2, which activates inflammatory responses in microglia. 120 The activation of the proinflammatory cascade was also reported in FTD patients with the P301S human tau-protein mutation. Activated microglia and infiltrating macrophages were detected in the cortex and hippocampus, along with IL-1 and cyclooxygenase-2 upregulation in neurons and glial cells, thus enhancing disease progression.…”

Section: Mechanisms Of Hypoperfusion-induced Neuroinflammation Inmentioning

confidence: 99%

The neuropathology and cerebrovascular mechanisms of dementia

Raz

Knoefel

Bhaskar

2015

J Cereb Blood Flow Metab

362

284

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The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer's Disease prioritized Alzheimer's disease-related dementias to include: Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and bloodbrain barrier permeability responsible for disease etiology and progression will be discussed.

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Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia

Cited by 698 publications

References 57 publications

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

The neuropathology and cerebrovascular mechanisms of dementia

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