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

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.

CB2 Receptor Deficiency Increases Amyloid Pathology and Alters Tau Processing in a Transgenic Mouse Model of Alzheimer’s Disease

“…In a mouse model expressing P301S-mutated tau, microglial activation preceded tangle formation, suggesting that inflammation may drive intraneuronal changes in tau processing (20). Lipopolysaccharide injection into the brains of mice expressing human mutant tau induces microglial activation and phosphorylation of tau (21,22). These data suggest that targeted interruption of inflammatory pathways in the absence of amyloid with cannabinoid therapies may influence tau processing and potentially tangle production.…”

Thinking laterally about neurodegenerative proteinopathies

“…There are more consistent data that indicate that proinflammatory stimuli may promote tau and α-synuclein pathology but also many fewer studies in this area (53). For example, LPS and various other proinflammatory stimuli have been shown to induce tau and α-synuclein pathology (65)(66)(67). Thus, at least in tau-and α-synuclein-opathies, there is evidence that a proinflammatory neurotoxic environment could induce or promote spread of pathology.…”

Effects of LPLI on microglial phagocytosis in LPS-induced neuroinflammation model

“…Signi¯cant elevations of cluster di®eren-tiation marker CD45, glial¯brillary acidic protein (GFAP), scavenger receptor A (SRA), and Fc receptor mRNA were seen after 24 h. 25 LPS-induced in°ammation also exacerbates phosphotau pathology in rTg4510 mice. 26 Much attention has been paid to therapeutic strategies aimed at controlling microglial-mediated neurotoxicity. LPLI is a nonthermal irradiation within the visible to near infrared range of light spectrum which has been used clinically to accelerate wound healing and reduce pain and in°am-mation in a variety of pathologies.…”