JOURNAL OF ALZHEIMERS DISEASE
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2015
·Vol. 49
·期 3
·829-844
·
IF 4.151
Shan Ye,Wang Dan-Dan,Xu Yu-Xia,Wang Chu,Cao Lan,Liu Yun-Sheng,Zhu Cui-Qing
Stress is an important risk factor of Alzheimer’s disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.
研究领域:
神经科学
·
药理学
·
老年学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2020
·
IF 4.486
Yuan Hu,Xiaochun Hu,Yonglin Lu,Shuo Shi,Danjing Yang,Tianming Yao
Inhibition of Tau protein aggregation is an attractive therapeutic target for Alzheimer’s disease. However, most of the inhibitors have failed in clinical trials due to the superficial understanding of inhibition mechanism and drug-transfer pharmacokinetics. Innovation of design strategy has become a top priority. To afford a hairpinlike molecular inhibitor, we introduced tannic acid, a multibranched polyphenol molecule, and its moiety, gallic acid. We showed that tannic acid could effectively inhibit Tau aggregation through a multidentate chelation mode. We then encapsulated tannic acid in a non-neurotoxic liposome by lecithin/β-sitosterol, overcoating with Tween 80. Using transwell devices, we cytologically demonstrated that tannic acid liposome can successfully be transferred across the model of a blood–brain barrier made up of mouse brain microvascular endothelial cell bEnd.3 and effectively reduce Tau aggregation induced by fibrils of Tau peptide R3 in human neuroblastoma cell SK-N-SH. This result indicates the potential therapeutic effect of tannic acid liposome on Alzheimer’s disease.
研究领域:
神经科学
·
药理学
·
分子生物学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2025
·
IF 3.9
Junjie Wu,Keke Chai,Ying Tu,Kang Fang,Shuo Shi,Xiaochun Hu,Jihong Liu,Tianming Yao
Tau aggregation inhibitors or neurotoxic-metal chelators have been extensively studied as potential treatment for Alzheimer’s disease. However, it is a great challenge to improve their therapeutic effects while reducing neurotoxicity. Herein, we designed and synthesized two new compounds, (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis((3,4,5-trihydroxyphenyl)methanone) ( 4GA ) and (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis((3,4,5-trihydroxyphenyl)methanone) ( 2GA ). Each molecule is composed of a 1,4,7,10-tetraazacyclododecane (cyclen) core as the supramolecular chelator to copper ions, attached by 2 or 4 gallic acid polyphenol arms to capture tau peptide chain like a molecular hairpin. We interestingly found 4GA and 2GA could inhibit self-aggregation through blocking the misfolding of tau peptide, suppress the promotion of Cu 2+ on tau aggregation by removing Cu 2+ from dyshomeostasis, and clear reactive oxygen species (ROS) triggered by Cu 2+ using their reductive gallic acid groups. More significantly, the synthesized compounds exhibit remarkable efficiency on both in vitro and at cellular level. Our rational design of multifunctional therapeutic agent that simultaneously targets tau misfolding process, copper dyshomeostasis and oxidative stress of ROS, may hold considerable implications for the treatment of AD.
研究领域:
神经科学
·
药物化学
·
生物无机化学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）