Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease

Tong, Xin‐Kang; Royea, Jessika; Hamel, Edith

doi:10.1038/s41419-022-04784-y

Cited by 16 publications

(11 citation statements)

References 89 publications

(103 reference statements)

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“…Previous studies have found that Wnt/βcatenin appears to be an important regulator of neurodegenerative diseases including AD. Because of the protective role of Wnt/β-catenin signaling in neurons, activation of Wnt/βcatenin signaling is considered to have potential value in the treatment of neurodegenerative diseases affecting synaptic integrity [64]. Previous studies have reported that β-catenin is downregulated in AD [65,66], which is consistent with our findings in Aβ 1-42 -induced PC12 cells.…”

Section: Discussionsupporting

confidence: 92%

Inhibition of VDAC1 Rescues Aβ1-42-Induced Mitochondrial Dysfunction and Ferroptosis via Activation of AMPK and Wnt/β-Catenin Pathways

Zhou

Tang

et al. 2023

Mediators of Inflammation

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Beta-amyloid (Aβ) accumulation in the brains of Alzheimer’s disease (AD) patients leads to mitochondrial dysfunction and ferroptosis in neurons. Voltage-dependent anion channel 1 (VDAC1) is a major protein in the mitochondrial outer membrane. It has been reported that VDAC1 associated with mitochondrial dysfunction and ferroptosis. However, the mechanism by which VDAC1 regulates mitochondrial dysfunction and ferroptosis of neurons in AD remains unclear. This study is aimed at investigating the mechanism of action of VDAC1 in mitochondrial dysfunction and ferroptosis in neurons of the AD model. In this study, we determined cell viability after treatment with Aβ1-42 via the MTT assay. The SOD, MDA, ROS, and MMP production was measured via the SOD kit, MDA kit, DCFDA staining, and JC-1 staining. The memory abilities of mice were detected via the Morris water maze test. The expression of AMPK/mTOR, Wnt/β-catenin, and GPX4 regulated by VDAC1 was detected via western blotting. Our present study showed that PC12 cells had decreased cell viability, increased LDH release, and decreased GPX4 expression after Aβ1-42 treatment. Meanwhile, Aβ1-42 induced MMP and SOD downregulation and increased MDA and ROS generation in PC12 cells. In addition, the expression of VDAC1 is increased in the brain tissue of AD mice and Aβ1-42-treated PC12 cells. Further investigation of the role of VDAC1 in regulating AD found that all effects induced by Aβ1-42 were reversed by inhibition of VDAC1. Additionally, inhibition of VDAC1 activates the AMPK/mTOR and Wnt/β-catenin pathways. Taken together, these findings demonstrate that inhibition of VDAC1 alleviates mitochondrial dysfunction and ferroptosis in AD neurons by activating AMPK/mTOR and Wnt/β-catenin.

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Section: Discussionsupporting

confidence: 92%

Inhibition of VDAC1 Rescues Aβ1-42-Induced Mitochondrial Dysfunction and Ferroptosis via Activation of AMPK and Wnt/β-Catenin Pathways

Zhou

Tang

et al. 2023

Mediators of Inflammation

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“…To determine whether the activation of β-catenin is essential for the TBK1-mediated promotion of EMT, XAV939 [ 26 , 27 ] was used to inhibit nuclear entry of β-catenin in TBK1-overexpressing cells. The results showed that inhibition of β-catenin nuclear entry blocked the TBK1-mediated upregulation of vimentin and the downregulation of E-cadherin (Fig.…”

Section: Resultsmentioning

confidence: 99%

Serine/threonine kinase TBK1 promotes cholangiocarcinoma progression via direct regulation of β-catenin

et al. 2023

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Cholangiocarcinoma (CCA) is a highly heterogeneous and metastatic malignancy with a poor prognosis even after curative hepatectomy. Studies exploring its pathogenesis and identifying effective therapeutic targets are urgently needed. In this study, we found that TANK-binding kinase 1 (TBK1), a serine/threonine-protein kinase, showed a dynamic increase during the different stages of murine spontaneous CCA carcinogenesis (hyperplasia, dysplasia, and CCA). TBK1 was upregulated in human tissues, including intrahepatic (n = 182) and extrahepatic (n = 40) CCA tissues, compared with nontumor tissues, and the elevated expression of TBK1 was positively correlated with larger tumour diameter, lymph node metastasis, and advanced TNM stage. Functional studies indicated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. TBK1 directly interacts with β-catenin, promoting its phosphorylation at the S552 site and its nuclear translocation, which further activates EMT-related transcriptional reprogramming. GSK-8612, a TBK1 inhibitor or a kinase-inactivating mutation, effectively suppresses the above processes. In addition, we found that low-density lipoprotein receptor (LDLR), which mediates the endocytosis of cholesterol, was upregulated in CCA. Therefore, we designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting TBK1 (Cho-TBK1-HDO), which could accumulate in CCA cells via LDLR, reduce the TBK1 mRNA level and inhibit intrahepatic metastasis of CCA. Besides, in the experimental group of 182 ICC patients, high TBK1 expression combined with high nuclear β-catenin expression predicted a worse prognosis. In summary, TBK1 might serve as a potential prognostic biomarker and therapeutic target for patients with CCA.

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“…Simvastatin is a frequently used statin included in various drug delivery systems and is widely used in the treatment of cardiovascular diseases [45,46], tumors [47] and Alzheimer's disease [48]. Dental implant osseointegration is a specific phenomenon of osteogenesis, and the promotion of osteogenesis can effectively promote dental implant osseointegration.…”

Section: Local Drugs Injectionmentioning

confidence: 99%

Effects of Hyperlipidemia on Osseointegration of Dental Implants and Its Strategies

Sun

Meng

Chen

et al. 2023

JFB

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Hyperlipidemia refers to the abnormal increase in plasma lipid level exceeding the normal range. At present, a large number of patients require dental implantation. However, hyperlipidemia affects bone metabolism, promotes bone loss, and inhibits the osseointegration of dental implants through the mutual regulation of adipocytes, osteoblasts, and osteoclasts. This review summarized the effects of hyperlipidemia on dental implants and addressed the potential strategies of dental implants to promote osseointegration in a hyperlipidemic environment and to improve the success rate of dental implants in patients with hyperlipidemia. We summarized topical drug delivery methods to solve the interference of hyperlipidemia in osseointegration, which were local drug injection, implant surface modification and bone-grafting material modification. Statins are the most effective drugs in the treatment of hyperlipidemia, and they also encourage bone formation. Statins have been used in these three methods and have been found to be positive in promoting osseointegration. Directly coating simvastatin on the rough surface of the implant can effectively promote osseointegration of the implant in a hyperlipidemic environment. However, the delivery method of this drug is not efficient. Recently, a variety of efficient methods of simvastatin delivery, such as hydrogels and nanoparticles, have been developed to boost bone formation, but few of them were applied to dental implants. Applicating these drug delivery systems using the three aforementioned ways, according to the mechanical and biological properties of materials, could be promising ways to promote osseointegration under hyperlipidemic conditions. However, more research is needed to confirm.

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Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease

Cited by 16 publications

References 89 publications

Inhibition of VDAC1 Rescues Aβ1-42-Induced Mitochondrial Dysfunction and Ferroptosis via Activation of AMPK and Wnt/β-Catenin Pathways

Inhibition of VDAC1 Rescues Aβ1-42-Induced Mitochondrial Dysfunction and Ferroptosis via Activation of AMPK and Wnt/β-Catenin Pathways

Serine/threonine kinase TBK1 promotes cholangiocarcinoma progression via direct regulation of β-catenin

Effects of Hyperlipidemia on Osseointegration of Dental Implants and Its Strategies

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