Stimulation of TLR4 Attenuates Alzheimer's Disease-Related Symptoms and Pathology in Tau-Transgenic Mice.
Alzheimer's disease (AD) is characterized by intracellular neurofibrillary tangles. The primary component, hyperphosphorylated Tau (p-Tau), contributes to neuronal death. Recent studies have shown that autophagy efficiently degrades p-Tau, but the mechanisms modulating autophagy and subsequent p-Tau clearance in AD remain unclear. In our study, we first analyzed the relationship between the inflammatory activation and autophagy in brains derived from aged mice and LPS-injected inflammatory mouse models. We found that inflammatory activation was essential for activation of autophagy in the brain, which was neuronal ATG5-dependent. Next, we found that autophagy in cultured neurons was enhanced by LPS treatment of cocultured macrophages. In further experiments designed to provoke chronic mild stimulation of TLR4 without inducing obvious neuroinflammation, we gave repeated LPS injections (i.p., 0.15 mg/kg, weekly for 3 mo) to transgenic mice overexpressing human Tau mutant (P301S) in neurons. We observed significant enhancement of neuronal autophagy, which was associated with a reduction of cerebral p-Tau proteins and improved cognitive function. In summary, these results show that neuroinflammation promotes neuronal autophagy and that chronic mild TLR4 stimulation attenuates AD-related tauopathy, likely by activating neuronal autophagy. Our study displays the beneficial face of neuroinflammation and suggests a possible role in the treatment of AD patients.
Department of Neurology, Second Affiliated Hospital, Soochow University, Suzhou 215123, China.|Institute of Neuroscience, Soochow University, Suzhou 215123, China.|Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany.|German Institute for Dementia Prevention, Saarland University, 66421 Homburg/Saar, Germany; and.
Yiren
Y
Qin
Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany; a.liu@mx.uni-saarland.de.|German Institute for Dementia Prevention, Saarland University, 66421 Homburg/Saar, Germany; and.
Yang
Y
Liu
Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany.|German Institute for Dementia Prevention, Saarland University, 66421 Homburg/Saar, Germany; and.
Wenlin
W
Hao
Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany.|German Institute for Dementia Prevention, Saarland University, 66421 Homburg/Saar, Germany; and.
Yann
Y
Decker
Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany.|German Institute for Dementia Prevention, Saarland University, 66421 Homburg/Saar, Germany; and.
Inge
I
Tomic
Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.
Michael D
MD
Menger
Department of Neurology, Second Affiliated Hospital, Soochow University, Suzhou 215123, China.|Institute of Neuroscience, Soochow University, Suzhou 215123, China.
Chunfeng
C
Liu
Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany.|German Institute for Dementia Prevention, Saarland University, 66421 Homburg/Saar, Germany; and.
Klaus
K
Fassbender
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
D008070:Lipopolysaccharides; C054369:MAPT protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016875:tau Proteins