Efficacy and mechanism of cGAMP to suppress Alzheimer’s disease by elevating TREM2

Xu, Qiming; Xu, Wei; Cheng, Hao; Yuan, Hong; Tan, Xiangshi

doi:10.1016/j.bbi.2019.07.004

Cited by 43 publications

(28 citation statements)

References 81 publications

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“…Neuroinflammation, driven mainly by activated microglia and astrocytes, is an early event and a critical pathological feature in the pathogenesis of AD [ 2 ]. Increasing evidence indicated that neuroinflammatory responses were closely associated with the progression of several AD-related neuropathological alterations, including Aβ deposition, neuronal dysfunction, tau pathology, and memory impairment [ 37 , 38 ]. Activated microglia and astrocytes produce a wide spectrum of pro-inflammatory cytokines and other mediators, which ultimately induce neuronal damage in the brain of AD.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro

Ding

Lin

Liu

et al. 2020

J Neuroinflammation

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Background Glial activation and neuroinflammation play a crucial role in the pathogenesis and development of Alzheimer’s disease (AD). The receptor for advanced glycation end products (RAGE)-mediated signaling pathway is related to amyloid beta (Aβ)-induced neuroinflammation. This study aimed to investigate the neuroprotective effects of tanshinone IIA (tan IIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza Bunge, against Aβ-induced neuroinflammation, cognitive impairment, and neurotoxicity as well as the underlying mechanisms in vivo and in vitro. Methods Open-field test, Y-maze test, and Morris water maze test were conducted to assess the cognitive function in APP/PS1 mice. Immunohistochemistry, immunofluorescence, thioflavin S (Th-S) staining, enzyme-linked immunosorbent assay (ELISA), real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and western blotting were performed to explore Aβ deposition, synaptic and neuronal loss, microglial and astrocytic activation, RAGE-dependent signaling, and the production of pro-inflammatory cytokines in APP/PS1 mice and cultured BV2 and U87 cells. Results Tan IIA treatment prevented spatial learning and memory deficits in APP/PS1 mice. Additionally, tan IIA attenuated Aβ accumulation, synapse-associated proteins (Syn and PSD-95) and neuronal loss, as well as peri-plaque microgliosis and astrocytosis in the cortex and hippocampus of APP/PS1 mice. Furthermore, tan IIA significantly suppressed RAGE/nuclear factor-κB (NF-κB) signaling pathway and the production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in APP/PS1 mice and cultured BV2 and U87 cells. Conclusions Taken together, the present results indicated that tan IIA improves cognitive decline and neuroinflammation partly via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro. Thus, tan IIA might be a promising therapeutic drug for halting and preventing AD progression.

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Section: Discussionmentioning

confidence: 99%

Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro

Ding

Lin

Liu

et al. 2020

J Neuroinflammation

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“…This novel pathway induces the release of mtDNA and further cytosolic detection by cGAS, but it is important to note that this discovery was made in monocytes and transformed lung cells (150). However, evidences indicate the presence of this axis in the CNS, as STING also modulates microglial reactivity during EAE (98,152,153). Moreover, the antiviral drug Ganciclovir promotes beneficial STING dependent type I IFN response in EAE model, dampening the harmful activity of activated microglia (154).…”

Section: A Sting In the Brainmentioning

confidence: 99%

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation

et al. 2021

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Neuroinflammatory and neurodegenerative diseases are a major public health problem worldwide, especially with the increase of life-expectancy observed during the last decades. For many of these diseases, we still lack a full understanding of their etiology and pathophysiology. Nonetheless their association with mitochondrial dysfunction highlights this organelle as an important player during CNS homeostasis and disease. Markers of Parkinson (PD) and Alzheimer (AD) diseases are able to induce innate immune pathways induced by alterations in mitochondrial Ca2+ homeostasis leading to neuroinflammation. Additionally, exacerbated type I IFN responses triggered by mitochondrial DNA (mtDNA), failures in mitophagy, ER-mitochondria communication and mtROS production promote neurodegeneration. On the other hand, regulation of mitochondrial dynamics is essential for CNS health maintenance and leading to the induction of IL-10 and reduction of TNF-α secretion, increased cell viability and diminished cell injury in addition to reduced oxidative stress. Thus, although previously solely seen as power suppliers to organelles and molecular processes, it is now well established that mitochondria have many other important roles, including during immune responses. Here, we discuss the importance of these mitochondrial dynamics during neuroinflammation, and how they correlate either with the amelioration or worsening of CNS disease.

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“…In contrast, the M2 phenotype shows a ramified morphology by secreting neurotrophic and antinflammatory factors to maintain homeostasis of the CNS environment [ 6 ]. Suppression of the microglial M1 phenotype and promotion of the transformation to the M2 phenotype have been reported to ameliorate chronic neurological disorders, such as AD [ 7 ], Parkinson’s disease [ 5 ], stroke [ 8 ], LPS-induced neuroinflammation [ 9 ], and exposure to electromagnetic field-induced neuroinflammation [ 10 ]. Studies have shown that microglia are in a state of overactivation in diabetic cognitive decline attributed to disordered glucose metabolism [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway

Long

Gao

et al. 2021

Brain Sciences

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Background: TREM2 expressed on microglia plays an important role in modulating inflammation in neurodegenerative diseases. It remains unknown whether TREM2 modulates hyperglycemia-induced microglial inflammation. Methods: We investigated the molecular function of TREM2 in high glucose-induced microglial inflammation using western blotting, qPCR, ELISA, pulldown, and co-IP methods. Results: Our data showed that in high glucose-induced BV2 cells, TREM2 was increased, and the proinflammatory cytokine IL-1β was increased. TREM2 knockout (KO) attenuated the proinflammatory cytokine IL-1β; conversely, TREM2 overexpression (OE) exacerbated IL-1β expression. Furthermore, we found that high glucose promoted the interaction of TREM2 with NLRP3. TREM2 KO abolished the interaction of TREM2 with NLRP3, while TREM2 OE enhanced the interaction. Moreover, TREM2 KO reduced high glucose-induced NLRP3 inflammasome activation, and TREM2 OE augmented high glucose-induced NLRP3 inflammasome activation, indicating that high glucose enhances the expression of TREM2, which activates the NLRP3 inflammasome. To further clarify whether the NLRP3 signaling pathway mediates the TREM2-regulated inflammatory response, we blocked the NLRP3 inflammasome by knocking out NLRP3 and treating cells with a caspase1 inhibitor, which decreased the levels of the IL-1β proinflammatory cytokine but did not affect the high glucose-induced expression of TREM2. Conclusions: TREM2 modulates high glucose-induced microglial inflammation via the NLRP3 signaling pathway.

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Efficacy and mechanism of cGAMP to suppress Alzheimer’s disease by elevating TREM2

Cited by 43 publications

References 81 publications

Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro

Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation

TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway

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