Journal Article

LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice

Reid, Patrick, Blair, Laura, Dickey, Chad A, Rizer, Justin, Kraft, Clara, Morgan, Dave, Selenica, Maj-Linda B, Lee, Daniel C, Johnson, Amelia, Gordon, Marcia N

2010

Overview

Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Aβ. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Aβ by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Age Factors / Alzheimer's disease / Analysis of Variance / Animals / Biomedical and Life Sciences / Biomedicine / Care and treatment / Complications and side effects / Data collection / Encephalitis - chemically induced / Encephalitis - metabolism / Encephalitis - pathology / Frontal Lobe - drug effects / Frontal Lobe - metabolism / Frontal Lobe - pathology / Glycoproteins / Health aspects / Hippocampus - drug effects / Hippocampus - metabolism / Hippocampus - pathology / Immunohistochemistry / Immunology / Inflammation / Lipopolysaccharides / Lipopolysaccharides - pharmacology / Mice / Mice, Transgenic / Microglia - drug effects / Microglia - metabolism / Microglia - pathology / Neurobiology / Neurofibrillary Tangles - metabolism / Neurofibrillary Tangles - pathology / Neurology / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neurosciences / Pathology / Phosphorylation - drug effects / Risk factors / Rodents / Silver Staining / tau Proteins - metabolism