Atorvastatin Attenuates Cognitive Deficits and Neuroinflammation Induced by Aβ1–42 Involving Modulation of TLR4/TRAF6/NF-κB Pathway

Abstract

Inflammatory damage aggravates the progression of Alzheimer's disease (AD) and the mechanism of inflammatory damage may provide a new therapeutic window for the treatment of AD. Toll-like receptor 4 (TLR4)-mediated signaling can regulate the inflammatory process. However, changes in TLR4 signaling pathway induced by beta-amyloid (Aβ) have not been well characterized in brain, especially in the hippocampus. In the present study, we explored the changes of TLR4 signaling pathway induced by Aβ in the hippocampus and the role of atorvastatin in modulating this signal pathway and neurotoxicity induced by Aβ. Experimental AD rats were induced by intrahippocampal injection of Aβ, and the rats were treated with atorvastatin by oral gavage from 3 weeks before to 6 days after injections of Aβ. To determine the spatial learning and memory ability of rats in the AD models, Morris water maze (MWM) was performed. The expression of the glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule-1 (Iba-1), TLR4, tumor necrosis factor receptor-associated factor 6 (TRAF6), and nuclear transcription factor (NF)-κB (NF-κB) protein in the hippocampus was detected by immunohistochemistry and Western blot. Compared to the control group, increased expression of TLR4, TRAF6, and NF-κB was observed in the hippocampus at 7 days post-injection of Aβ (P < 0.01). Furthermore, atorvastatin treatment significantly ameliorated cognitive deficits of rats, attenuated microglia and astrocyte activation, inhibited apoptosis, and down-regulated the expression of TLR4, TRAF6, and NF-κB, both at the mRNA and protein levels (P < 0.01). TLR4 signaling pathway is thus actively involved in Aβ-induced neuroinflammation and atorvastatin treatment can exert the therapeutic benefits for AD via the TLR4 signaling pathway.

TET2 Regulates the Neuroinflammatory Response in Microglia

“…For instance, a-synuclein aggregates induce microglial activation (Boza-Serrano et al, 2014) in a TLR-4-dependent manner (Fellner et al, 2013). Similarly, the fibrillar and oligomeric Ab induce also a TLR-4-dependent immune response (Reed-Geaghan et al, 2009;Wang et al, 2018). BV2 cells were treated with a-synuclein aggregates and Ab oligomers for 6 h, which produced an increase of Tet2 expression similar to that observed with LPS ( Figure S7A).…”

The progress of gut microbiome research related to brain disorders

“…The downstream inflammatory cytokine TNF-α further reduces neurogenesis and induces the proliferation of astrocytes [45]. There is also evidence that TLR4 is related to the development of learning and memory [46,47].…”

The effects of statins on microglial cells to protect against neurodegenerative disorders: A mechanistic review

“…Further to this, TRAF6 mediates the signaling not only from TNF receptor superfamily, but also from Toll/IL‐1 family members . Recently, new evidence has illustrated that statins can attenuate TRAF6 production …”

“…There is a growing body of evidence on the effects of various statins on CNS cells, especially microglial cells, to promote the neurogenesis, synaptogenesis, anti‐neuroinflammation, improve angiogenesis, prevent superoxide free radicals, neurofunctional rehabilitation and improve phagocytic activity . In addition, recent evidence suggests that specific statins can inhibit or alter the microglia inflammatory inducers/mediators and their subsequent productions including IL‐1β, MMP‐9, PGE2, IFN‐γ, TNF‐α, COX‐2, ROS/NO production, Aβ (Aβ40 and Aβ42 variants), peroxisome proliferator‐activated receptor‐gamma (PPARγ), and JNK and p38 MAPK . Herein, given the proven association between neuroinflammation and progression the NDs, we reviewed in details about the statins anti‐inflammatory property and their underlying mechanisms of one of the most primary CNS cells, the microglia.…”