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

Abstract

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.

Ginsenoside Rg1 improves cognitive capability and affects the microbiota of large intestine of tree shrew model for Alzheimer's disease

“…Jiang et al ( 37 ) demonstrated that the decrease of MAP2 in dendrites shows that neurodegeneration leads to neuron death. Neurodegeneration and neuron loss are features of the hippocampus and cortex in AD, making them potential targets for AD treatment strategies ( 38 ). Kandimalla et al ( 39 ) demonstrated that the accumulation of phosphorylated tau in the hippocampus results in abnormal mitochondrial dynamics and reduces the dendritic protein MAP2, resulting in learning and memory impairment ( 40 ).…”

Systematic Search for Novel Circulating Biomarkers Associated with Extracellular Vesicles in Alzheimer’s Disease: Combining Literature Screening and Database Mining Approaches

“…TLR2 are one of the most studied pattern recognition receptors that recognize pathogens and initiate the cascade of host defense mechanisms [92]. The activation of TLR2 induces neurodegeneration and cognitive deficit in AD murine models [93,94]. Further evidence elucidated the role of immune system in AD development, including TLR2 polymorphisms associated with AD in Asian populations [95,96].…”

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

“…Several TLR4 inhibitors improved cognitive deficits in AD animal models, including thymoquinone, ethyl pyruvate, and TAK-242 [ 68 ]. TLR2 binds to Aβ and mediates the Aβ phagocytosis by microglia [ 207 ]. Dysregulation of the TLR2 pathway accelerated memory impairment in AD mice, either through inhibition [ 208 , 209 , 210 ] or activation [ 207 ].…”

“…TLR2 binds to Aβ and mediates the Aβ phagocytosis by microglia [ 207 ]. Dysregulation of the TLR2 pathway accelerated memory impairment in AD mice, either through inhibition [ 208 , 209 , 210 ] or activation [ 207 ]. None of these agents have reached clinical trials for AD therapy.…”