Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease.
Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a transgenic model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloidbeta-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.
Kitazawa
Masashi
M
Department of Neurobiology and Behavior, University of California-Irvine, California 92697-4545, USA.
Oddo
Salvatore
S
Yamasaki
Tritia R
TR
Green
Kim N
KN
LaFerla
Frank M
FM
D000375:Aging; D000544:Alzheimer Disease; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D004789:Enzyme Activation; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia; D009434:Neural Pathways / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D024801:Tauopathies / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism
D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011687:Purines; D016875:tau Proteins; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5