Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer’s pathology

Rangasamy, Suresh B.; Jana, Malabendu; Roy, Avik; Corbett, Grant T.; Kundu, Manjari; Chandra, Sujyoti; Mondal, Sourav; Dasarathi, Sridevi; Mufson, Elliott J.; Mishra, Rama K.; Luan, Chi Hao; Bennett, David A.; Pahan, Kalipada

doi:10.1172/jci96209

Cited by 111 publications

(119 citation statements)

References 59 publications

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“…TLR2 mediates Aβ ingestion by microglia, and its blockage results in amyloid accumulation [23]. Furthermore, disruption of downstream TLR2 signaling prevented the progression of AD pathology in AD transgenic mice [30]. However, Aβ deposition is probably not associated directly with neurodegeneration [6,12], suggesting that other superimposing insults, such as external TLR2 agonists, may be involved in the progressive loss of cortical neurons.…”

Section: Introductionmentioning

confidence: 99%

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Lax

Fainstein

Nishri

et al. 2020

J Neuroinflammation

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Background: Accumulating data suggest a central role for brain microglia in mediating cortical neuronal death in Alzheimer's disease (AD), and for Toll-like receptor 2 (TLR2) in their toxic activation. Amyloid deposition in preclinical AD is associated with microglial activation but not directly with neurodegeneration. We examined in transgenic 5xFAD mice the hypothesis that systemic TLR2 agonists, derived from common infectious agents, may accelerate neurodegeneration in AD. Methods: Microbial wall-derived TLR2 agonists zymosan and lipoteichoic acid were administered intraperitoneally or intracerebroventricularly to 7-month-old wild-type or 5xFAD mice. Immunofluorescent stainings were used to quantify cortical neurons and evaluate tissue reaction. Microglial activation was assessed using functional assays, RNA expression, and FACS analysis. Results: Repeated low-dose systemic administration of zymosan or lipoteichoic acid killed cortical neurons in 5xFAD mice but not in wild-type mice. Direct CNS delivery of a selective TLR2 antagonist blocked the neurotoxicity of systemically administered zymosan, indicating that CNS TLR2 mediates this effect. Systemically administered zymosan crossed the disrupted blood-brain barrier in 5xFAD mice and entered brain parenchyma. By intracerebroventricular delivery, we found a dose-and exposure time-dependent acute neurotoxic effect of the microbial TLR2 agonist, killing cortical neurons. 5xFAD mice exhibited significantly increased vulnerability to TLR2 agonist-induced neuronal loss as compared to wild-type mice. Microbial TLR2-induced neurodegeneration was abolished by inhibiting microglia. The vulnerability of 5xFAD mice brains was mediated by an increase in number and neurotoxic phenotype of TLR2expressing microglia. Conclusions: We suggest that repeated exposure to microbial TLR2 agonists may facilitate neurodegeneration in AD by their microglial-mediated toxicity to the hyper-vulnerable environment of the AD brain.

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Section: Introductionmentioning

confidence: 99%

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Lax

Fainstein

Nishri

et al. 2020

J Neuroinflammation

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“…Environmental factors, such as trauma and stressful life events, profoundly alter neural structure and functional plasticity of the brain, drives changes in physiology and behavior, and contributes to a variety of mental disorders [5]. Although the mechanism underlying PICS remains largely unexplored, the pathobiology of psychiatric conditions is closely linked to inflammatory processes [22][23][24]. Similarly, we showed signs of hippocampal inflammation in the form of glia overactivation and hypersecretion of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 55%

“…Indeed, earlier studies have shown that chronic stress is associated with a chronic, low-grade inflammation in other models of neurodegenerative diseases [22][23][24][25]. Since we used a combined stress protocol, LPS challenge may act as an early toxic event and render the brain susceptible to subsequent chronic stress.…”

Section: Discussionmentioning

confidence: 99%

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

Ji¹,

Tong²,

Zhou³

et al. 2020

Preprint

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Background Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness, which is associated with reduced quality of life and increased mortality. We recently have developed a clinically relevant animal model of PICS, which can mimic most features of human PICS. However, the underlying mechanism remains largely to be elucidated. Accumulating evidence has suggested that hippocampal GABAergic interneuron dysfunction is implicated in various mood disorders induced by stress. Methods We explored the role of hippocampal GABAergic interneurons and relevant neural activities in an animal model of PICS based on two-hit hypothesis. In addition, we tested whether fluoxetine treatment early following combined stress can prevent subsequent anatomical and behavioral pathologies. Results Here our study further supported our previous findings that this PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments, which resembles clinical features of human PICS. This behavioral state is accompanied by hippocampal neuroinflammation, reduced parvalbumin (PV) expression, and decreased theta and gamma power. Importantly, chronic fluoxetine treatment reversed most of these abnormities. Conclusions Our study provides additional evidence that PV interneuron-mediated hippocampal network activity disruption might play a key role in the pathological of PICS, while fluoxetine offers protection via modulation of the hippocampal PV interneuron and relevant network activities.

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“…In this context, it was observed that a TLR2binding peptide (WT TIDM) inhibited Aβ-induced microglial activation, reduced Aβ load, attenuated neuronal apoptosis, and improved memory and learning in mice. However, WT TIDM peptide was not effective in TLR2 knockout mice [29].…”

Section: Toll-like Receptorsmentioning

confidence: 91%

Alzheimer’s Disease Neuroprotection: Associated Receptors

Câmara¹

2020

Neuroprotection - New Approaches and Prospects

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Research with humans and animals has been developed over the past few years to identify receptors involved in Alzheimer's disease, aiming at a better understanding of the mechanisms and pathophysiological aspects associated with the disease. Such receptors, whether or not directly associated with current AD therapy, are relevant since their blockage or activation might result in improving or worsening the clinical scenario of the disease. In other words, such receptors might be involved in the AD prognosis. This chapter discusses some relevant points about the receptors involved with AD.

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Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer’s pathology

Cited by 111 publications

References 59 publications

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Parvabumin interneuron-mediated hippocampal network activity disruption in a two-hit model with relevance to postintensive care syndrome: prevention by fluoxetine

Alzheimer’s Disease Neuroprotection: Associated Receptors

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