TREM2 Inhibits Tau Hyperphosphorylation and Neuronal Apoptosis via the PI3K/Akt/GSK-3β Signaling Pathway In vivo and In vitro.

Triggering receptor expressed on myeloid cells-2 (TREM2), a cell surface receptor mainly expressed on microglia, has been shown to play a critical role in Alzheimer's disease (AD) pathogenesis and progression. Our recent results showed that overexpression of TREM2 inhibited inflammatory response in APP/PS1 mice and BV2 cells. Several studies indicated that TREM2 ameliorated tau hyperphosphorylation might be ascribed to the inhibition of neuroinflammation. However, the precise signaling pathways underlying the effect of TREM2 on tau pathology and neuronal apoptosis have not been fully elucidated. In the present study, upregulation of TREM2 significantly inhibited tau hyperphosphorylation at Ser199, Ser396, and Thr205, respectively, as well as prevented neuronal loss and apoptosis. We also found that upregulation of TREM2 alleviated behavioral deficits and improved the spatial cognitive ability of APP/PS1 mice. Further study revealed that TREM2 could activate phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, resulting in an inhibitory effect on glycogen synthase kinase-3β (GSK-3β), which is a major kinase responsible for tau hyperphosphorylation in AD. In line with in vivo findings, TREM2-overexpressing BV2 microglia following β-amyloid (Aβ) stimulation led to a significant increase in the phosphorylation of PI3K, Akt, and GSK-3β, accompanied by a decrease in tau hyperphosphorylation and apoptosis in co-cultured SH-SY5Y cells. Furthermore, LY294002, a specific PI3K inhibitor, was observed to abolish the beneficial effects of TREM2 on tau hyperphosphorylation, neuronal apoptosis, and spatial cognitive impairments in vivo and in vitro. Thus, our findings indicated that TREM2 inhibits tau hyperphosphorylation and neuronal apoptosis, at least in part, by the activation of the PI3K/Akt/GSK-3β signaling pathway. Taken together, the above results allow us to better understand how TREM2 protects against tau pathology and suggest that upregulation of TREM2 may provide new ideas and therapeutic targets for AD.

Peng X ，Guo H ，Zhang X ，Yang Z ，Ruganzu JB ，Yang Z ，Wu X ，Bi W ，Ji S ，Yang W ... -  《-》

Tanshinone IIA regulates glycogen synthase kinase-3β-related signaling pathway and ameliorates memory impairment in APP/PS1 transgenic mice.

Our previous findings indicated that tanshinone IIA (tan IIA), a natural component extracted from the root and rhizome of danshen, significantly attenuated β-amyloid accumulation, neuroinflammation, and endoplasmic reticulum stress, as well as improved learning and memory deficits in APP/PS1 transgenic mouse model of Alzheimer's disease (AD). However, whether tan IIA can ameliorate tau pathology and the underlying mechanism in APP/PS1 mice remains unclear. In the current study, tan IIA (15 mg/kg and 30 mg/kg) or saline was intraperitoneally administered to the 5-month-old APP/PS1 mice once daily for 4 weeks. The open-field test, novel object recognition test, Y-maze test, and Morris water maze test were performed to assess the cognitive function. Nissl staining, immunohistochemistry, TUNEL, and western blotting were conducted to explore tau hyperphosphorylation, neuronal injury, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3β (GSK-3β) signaling pathway. The activity of GSK-3β, acetylcholinesterase (AChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) were measured using commercial kits. Our results revealed that tan IIA treatment significantly ameliorated behavioral deficits and improved spatial learning and memory ability of APP/PS1 mice. Additionally, tan IIA markedly attenuated tau hyperphosphorylation and prevented neuronal loss and apoptosis in the parietal cortex and hippocampus. Simultaneously, tan IIA reversed cholinergic dysfunction and reduced oxidative stress. Furthermore, tan IIA activated the PI3K/Akt signaling pathway and suppressed GSK-3β. Taken together, the above findings suggested that tan IIA improves cognitive decline and tau pathology may through modulation of PI3K/Akt/GSK-3β signaling pathway.

Peng X ，Chen L ，Wang Z ，He Y ，Ruganzu JB ，Guo H ，Zhang X ，Ji S ，Zheng L ，Yang W ... -  《-》

TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice.

As a novel risk gene for Alzheimer's disease (AD), triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes a type I transmembrane receptor that is uniquely expressed by the microglia in the brain. Emerging evidence indicates a strong association between TREM2 and tau pathology in the cerebral spinal fluid or brain tissue of AD patients. In line with these clinical findings, we found that TREM2 was upregulated in the brain of P301S mice, an animal model of tau pathology, during disease progression. However, despite this information, the precise role of TREM2 in tau pathology remains largely unknown. In our recent studies, we revealed that silencing microglial TREM2 expression in P301S mice exacerbated spatial cognitive deficits and tau pathology. Based on this evidence, we hypothesized that TREM2 might exert a protective effect in tau-related neurodegenerative diseases. In the present study, to test this hypothesis, a lentiviral-mediated strategy was employed to selectively overexpress TREM2 on microglia in the brain of P301S mice. For the first time, we showed that TREM2 overexpression rescued spatial cognitive impairments and ameliorated neuropathologies including neuronal and synaptic loss as well as tau hyperphosphorylation. Meanwhile, this protective effect was likely attributed to the suppression of neuroinflammation and subsequent attenuation of tau kinase activity, since the expression of pro-inflammatory cytokines including Tnf, Il1b and Il6 as well as the activity of tau kinase including glycogen synthase kinase 3β and cyclin-dependent kinase 5 was significantly reduced following TREM2 overexpression. Additionally, the suppressed neuroinflammation might be ascribed to the M2 activation of microglia induced by TREM2, as the expression of M2 phenotype makers including Arg1, Retnla, Il4 and Il10 was markedly increased. Taken together, these findings support the concept of TREM2 as a valuable target against AD as well as other tau-related neurodegenerative diseases.

Jiang T ，Zhang YD ，Chen Q ，Gao Q ，Zhu XC ，Zhou JS ，Shi JQ ，Lu H ，Tan L ，Yu JT ... -  《-》

Naringin Protects against Tau Hyperphosphorylation in Aβ (25-35)-Injured PC12 Cells through Modulation of ER, PI3K/AKT, and GSK-3β Signaling Pathways.

Alzheimer's disease (AD) is the most common form of dementia and a significant social and economic burden. Estrogens can exert neuroprotective effects and may contribute to the prevention, attenuation, or even delay in the onset of AD; however, long-term estrogen therapy is associated with harmful side effects. Thus, estrogen alternatives are of interest for countering AD. Naringin, a phytoestrogen, is a key active ingredient in the traditional Chinese medicine Drynaria. Naringin is known to protect against nerve injury induced by amyloid beta-protein (Aβ) 25-35, but the underlying mechanisms of this protection are unclear. To investigate the mechanisms of naringin neuroprotection, we observed the protective effect on Aβ 25-35-injured C57BL/6J mice's learning and memory ability and hippocampal neurons. Then, an Aβ 25-35 injury model was established with adrenal phaeochromocytoma (PC12) cells. We examined the effect of naringin treatment on Aβ 25-35-injured PC12 cells and its relationship with estrogen receptor (ER), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase (GSK)-3β signaling pathways. Estradiol (E2) was used as a positive control for neuroprotection. Naringin treatment resulted in improved learning and memory ability, the morphology of hippocampal neurons, increased cell viability, and reduced apoptosis. We next examined the expression of ERβ, p-AKT (Ser473, Thr308), AKT, p-GSK-3β (Ser9), GSK-3β, p-Tau (Thr231, Ser396), and Tau in PC12 cells treated with Aβ 25-35 and either naringin or E2, with and without inhibitors of the ER, PI3K/AKT, and GSK-3β pathways. Our results demonstrated that naringin inhibits Aβ 25-35-induced Tau hyperphosphorylation by modulating the ER, PI3K/AKT, and GSK-3β signaling pathways. Furthermore, the neuroprotective effects of naringin were comparable to those of E2 in all treatment groups. Thus, our results have furthered our understanding of naringin's neuroprotective mechanisms and indicate that naringin may comprise a viable alternative to estrogen therapy.

Qiu Q ，Lei X ，Wang Y ，Xiong H ，Xu Y ，Sun H ，Xu H ，Zhang N ... -  《-》

Dendrobium nobile Lindl. alkaloid decreases Tau hyperphosphorylation via regulating PI3K/Akt/GSK-3β pathway in vitro and in vivo.

Huang J ，Huang N ，Qiu Y ，Shi J ... -  《-》