Abstract
BackgroundAccumulating 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.MethodsMicrobial 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.ResultsRepeated 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 TLR2-expressing microglia.ConclusionsWe 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.
Highlights
Accumulating evidence suggests that the neurodegenerative process in Alzheimer’s disease (AD) is driven by the neurotoxic effect of activated microglia [20, 37]
Systemic Toll-like receptor 2 (TLR2) agonists induce neurodegeneration in 5xFAD brains by penetrating the Central nervous system (CNS) Multiple types of common microorganisms express TLR2 agonists that may be released to the systemic circulation during infectious events
We examined whether systemic administration of two types of microbial wall-derived TLR2 agonists can cause loss of cortical neurons by quantifying NeuN + cells
Summary
Accumulating evidence suggests that the neurodegenerative process in AD is driven by the neurotoxic effect of activated microglia [20, 37]. It has been suggested that systemic infections might activate inflammatory cells in the brain and especially microglia to exacerbate disease Direct intracerebroventricular (ICV) delivery of the microbial TLR2 agonist showed a dose- and exposure time-dependent neurotoxic effect, and a significantly increased vulnerability of AD mice to the TLR2 agonist as compared with wild-type mice. We suggest that repeated infections, with exposure to microbial TLR2 agonists, may facilitate neurodegeneration in the hypervulnerable environment of the AD brain, an effect mediated by microglial toxicity. 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. We examined in transgenic 5xFAD mice the hypothesis that systemic TLR2 agonists, derived from common infectious agents, may accelerate neurodegeneration in AD
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