Abstract
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.
Highlights
Tauopathies consist of intracellular accumulation of the microtubule-associated protein tau in the somatodendritic compartment associated with hyperphosphorylation and aggregation of the protein
In this study, we show that the phosphorylated tau species previously characterized in the rTg4510 mice [30] are associated with age-related microglial activation as measured by CD45 Further activation of microglia by LPS enhances tau phosphorylation
By 5.5 months, insoluble tau aggregates appear in parallel with accumulation of a 64 kD soluble tau species
Summary
Tauopathies consist of intracellular accumulation of the microtubule-associated protein tau in the somatodendritic compartment associated with hyperphosphorylation and aggregation of the protein. Numerous studies targeting different components of the disease have been initiated to reduce tau pathology as well as amyloid-b. These include inhibition of kinases which phosphorylate tau, such as glycogen synthase kinase-3b (GSK3b) [5,6,7,8], manipulating heat shock proteins [9,10,11], immunotherapy which targets the tau peptide and subsequently reduces p-tau levels, [12,13], and modifying p-tau by manipulating the Inflammation arguably plays a significant role in the progression of AD pathology. As more studies emerge identifying selective markers that represent different phenotypic activation states of microglia, an association of their role during disease pathology is being revealed. Some reports suggest that in chronic neurodegenerative diseases like AD, a hybrid activation state exists including markers of both M1 and
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