Regulation of Tau Pathology by the Microglial Fractalkine Receptor

Bhaskar, Kiran; Konerth, Megan E.; Kokiko-Cochran, Olga N.; Cardona, Astrid E.; Ransohoff, Richard M.; Lamb, Bruce T.

doi:10.1016/j.neuron.2010.08.023

Cited by 536 publications

(603 citation statements)

References 49 publications

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“…On the basis of described results that KOR in microglia protects neurons from endotoxin-induced neurotoxicity, and given that b-arrestin arrests inflammatory microglia X Feng et al endotoxin-induced neurotoxicity is mainly mediated by the increased production of pro-inflammatory cytokines, 30 we then determined how KOR affects microglial cytokine activity in response to LPS treatment. Figure 2a shows that the gene expression level of inflammatory mediators IL-1b, TNF-a, and inducible nitric oxide synthase (iNOS) was significantly increased in Kor À / À microglia compared with WT microglia after LPS treatment.…”

Section: Resultsmentioning

confidence: 99%

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Feng

Burton

et al. 2013

Cell Death Differ

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Microglial activation worsens neuronal loss and contributes to progressive neurological diseases like Parkinson's disease (PD). This inflammatory progression is countered by dynorphin (Dyn), the endogenous ligand of the kappa-opioid receptor (KOR). We show that microglial b-arrestin mediates the ability of Dyn/KOR to limit endotoxin-elicited production of pro-inflammatory effectors and cytokines, subsequently protecting neurons from inflammation-induced neurotoxicity. Agonist-activated KOR enhances the interaction of b-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1), disrupting TAK1-TAB1 mediated pro-inflammatory gene expression. We reveal a new physiological role for b-arrestin in neuroprotection via receptor internalization-triggered blockade of signal effectors of microglial inflammatory neurotoxicity. This result offers novel drug targets in the convergent KOR/b-arrestin2 and inflammatory pathways for treating microglial inflammatory neuropathologies like PD. Cell Death and Differentiation (2014) 21, 397-406; doi:10.1038/cdd.2013 published online 25 October 2013 Increasing evidence suggests that the overactivation of immune system-derived microglia in the substantia nigra (SN) is a key causative factor in the pathogenesis of Parkinson's disease (PD), the most prevalent neurodegenerative disease in the population over 60 years old. Pathologically, PD is characterized by the degeneration of dopaminergic (DA) neurons of the SN pars compacta (SNpc) in the midbrain, leading to disabled voluntary movements. Immunohistochemistry research has indicated that activated microglia accumulate around degenerating neurons in the SN of patients with PD and related parkinsonian syndromes. 1 Although microglial activation in these diseases is not limited to the SN, the DA neurons in the SN are particularly vulnerable to inflammatory insult owing to the larger population of microglia in the SN. 2,3 As a sensor of brain injury and aging, microglia's state and activity are regulated through neuronmicroglia communication involving the stimulation of signal transducing or phagocytic microglial receptors by neurotransmitters. 4,5 Deficiencies in this communication between neurons and microglia as a result of stress or aging leads to reactive microglia and prolonged inflammation and, as a result, neuronal death. Similarly, stimulation of microglia by bacteria or endotoxins results in outbursts of pro-inflammatory cytokines such as interleukin 1 beta (IL-1b), tumor necrosis factor-a (TNF)-a, and interleukin 6 (IL-6) through activation of toll-like receptor 4 (TLR4). This can contribute to the death of neurons in the SN because long-term inhibition of IL-1b and TNF-a has consistently been reported to attenuate tyrosine hydroxylase (TH þ ) neuron loss in PD models. 6,7 Meanwhile, neuron degeneration itself leads to further secondary activation of microglia via increased production of matrix metalloproteinase 3 and neuromelaine and, as a result, further neuronal death. [8][9][10] Thus...

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Section: Resultsmentioning

confidence: 99%

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Feng

Burton

et al. 2013

Cell Death Differ

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“…[88][89][90] Similarly, a recent study showed that induced airway allergy in mice modified the brain inflammatory status and increased phosphorylation of tau. 91 Given that phosphorylation of tau is crucial for regulation of microtubule stability and axonal transport, 92 and that hyperphosphorylated tau not only affects the microtubule network but also induces accumulation of filamentous actin and formation of actin-rich rods, 93 these observations could provide a link between inflammatory processes and cytoskeletal abnormalities observed in postmortem examination of all AD cases.…”

Section: Early Cytoskeletal Impairmentsmentioning

confidence: 94%

“…Systemic administration of LPS, a potent inflammatory agent, induces hyperphosphorylation of tau in neurons 88 -a process that is mediated by activated microglia. [88][89][90] Similarly, a recent study showed that induced airway allergy in mice modified the brain inflammatory status and increased phosphorylation of tau.…”

Section: Early Cytoskeletal Impairmentsmentioning

confidence: 99%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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“…These pathologic markers positively correlate with neuronal degeneration, neuroinflammation, microglia activation, BBB dysfunction, and cognitive decline. 27,28 Furthermore, NFT pathology in AD develops in three stages: transentorhinal, limbic, and isocortical, which is the basis of the Braak and Braak staging system of AD, 29 and serves as a better predictor of cognitive decline as compared with A pathology. 30 As a detailed discussion of AD characterization and clinical diagnosis is beyond the scope of the review, the reader is referred to current comprehensive reviews on the topic.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

The neuropathology and cerebrovascular mechanisms of dementia

Raz

Knoefel

Bhaskar

2015

J Cereb Blood Flow Metab

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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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Regulation of Tau Pathology by the Microglial Fractalkine Receptor

Cited by 536 publications

References 49 publications

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Deciphering the mechanism underlying late-onset Alzheimer disease

The neuropathology and cerebrovascular mechanisms of dementia

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