Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Abstract

Neuroinflammation plays a key role in the pathogenesis of Alzheimer’s disease and related tauopathies. We have previously shown that expression of nonmutated human truncated τ (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated τ. We found that purified recombinant truncated τ induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated τ caused the release of NO, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated τ, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the τ-mediated inflammatory response. Molecular analysis showed that truncated τ increased the mRNA levels of three MAPKs (JNK, ERK1, p38β) and transcription factors AP-1 and NF-κB that ultimately resulted in enhanced mRNA expression of IL-1β, IL-6, TNF-α, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein τ is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein τ represents a viable target for immunotherapy of Alzheimer’s disease.

High molecular weight polysaccharides are key immunomodulators in North American ginseng extracts: Characterization of the ginseng genetic signature in primary human immune cells

“…These pathways are involved in the production of pro-inflammatory cytokines (Buhrmann et al, 2011;Kovac et al, 2011;Sun et al, 2011) and have previously been shown to be induced by GS extract stimulation in PBMC (Toth et al, 2010). In addition, these pathways are also involved in other biological activities of GS such as decreasing ischemic reperfusion injury , killing of tumors (Ming et al, 2011;Wong et al, 2010) and reducing damage from oxidative stress .…”

Roles of tau protein in health and disease

“…Exposure of extracellular misfolded truncated tau activates microglia through the MAPK pathway and induces the production of pro-inflammatory cytokines, including Interleukin-1β, Interleukin-6 and tumour necrosis factor alpha [263], which promote tau phosphorylation inside neurons [543]. Moreover, activated microglia may directly mediate tau propagation.…”

Microglia display modest phagocytic capacity for extracellular tau oligomers

“…Several previous studies have demonstrated that extracellular tau proteins play an important role in AD neuroinflammation [28–30]. It was shown that the oligomeric tau that represents an early stage of tangle formation can be released into the extracellular space, where it behaves as a transmissible agent, spreading tau pathology throughout the brain in a ‘prion-like fashion’ [31–33].…”