المؤلفون: Ghosh, Anamitra, Comerota, Michele M, Wan, Debin, Chen, Fading, Propson, Nicholas E, Hwang, Sung Hee, Hammock, Bruce D, Zheng, Hui

المصدر: Science Translational Medicine. 12(573)

مصطلحات موضوعية: Medical Biotechnology, Biomedical and Clinical Sciences, Neurodegenerative, Neurosciences, Aging, Alzheimer's Disease, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer Disease, Animals, Epoxide Hydrolases, Epoxy Compounds, Humans, Mice, Phenylurea Compounds, Piperidines, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering

الوصف: Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer's disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited because of their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and is elevated in postmortem brain tissue from patients with AD and in the 5xFAD β amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small-molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected wild-type mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement of this small molecule. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1j43s94cTest
https://escholarship.org/content/qt1j43s94c/qt1j43s94c.pdfTest

المؤلفون: Zhao, Peng, Xu, Yuanzhong, Jiang, LuLin, Fan, Xuejun, Li, Leike, Li, Xin, Arase, Hisashi, Zhao, Yingjun, Cao, Wei, Zheng, Hui, Xu, Huaxi, Tong, Qingchun, Zhang, Ningyan, An, Zhiqiang

المصدر: Science Translational Medicine; 9/7/2022, Vol. 14 Issue 661, p1-15, 15p

مصطلحات موضوعية: ALZHEIMER'S disease, LABORATORY mice, TRANSFERRIN receptors, AMYLOID, ANIMAL disease models, PATHOLOGY, TRANSFERRIN, MONOCLONAL antibodies

مستخلص: Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in Alzheimer's disease (AD) by regulating microglia migration toward, and phagocytosis of oligomeric amyloid-β (oAβ) and amyloid plaques. Studies in rodent models of AD have shown that mice with increased TREM2 expression have reduced amyloid pathology. Here, we identified a TREM2 agonist monoclonal Ab (Ab18) by panning a phage-displayed single-chain variable fragment Ab library. By engineering the bivalent immunoglobulin G1 (IgG1) to tetra-variable domain immunoglobulin (TVD-Ig), we further increased the TREM2 activation by 100-fold. Stronger TREM2 activation led to enhanced microglia phagocytosis of the oAβ-lipid complex, migration toward oAβ, and improved microglia survival in vitro. Mechanistic studies showed increased TREM2 clustering on microglia by the tetravalent Ab18 TVD-Ig without altering microglial TREM2 amount. An engineered bispecific Ab targeting TREM2 and transferrin receptor (TfR; Ab18 TVD-Ig/αTfR) improved Ab brain entry by more than 10-fold with a broad brain parenchyma distribution. Weekly treatment of 5XFAD mice (a model of AD) with Ab18 TVD-Ig/αTfR showed a considerable reduction of amyloid burden with increased microglia migration to and phagocytosis of amyloid plaques, improved synaptic and neuronal marker intensity, improved cognitive functions, reduced endogenous tau hyperphosphorylation, and decreased phosphorylated neurofilament H immunostaining. This study demonstrated the feasibility of engineering multivalent TREM2 agonistic Ab coupled with TfR-mediated brain delivery to enhance microglia functions and reduce amyloid pathology in vitro and in vivo. This Ab engineering approach enables the development of effective TREM2-targeting therapies for AD. Leveraging immunity for TREM2 activation: The receptor TREM2 has been shown to play an important role in the pathophysiology of Alzheimer's disease (AD), and recent data suggest that increasing TREM2 activation could have therapeutic effects. Here, Zhao et al. developed a TREM2 agonistic Ab that strongly increased TREM2 activation and promoted Aβ oligomers phagocytosis and microglia survival in coculture experiments. By engineering the Ab, the authors increased its potency and improved brain penetrance. In vivo treatment in a mouse model of AD had therapeutic effects, including increased microglia-mediated phagocytosis and improved cognition, among other effects. The results suggest that Ab-mediated TREM2-targeting therapies might be effective in reducing AD pathology. [ABSTRACT FROM AUTHOR]

: Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Yu, Hojeong, Lee, Hoyeon, Cheong, Jiyong, Woo, Sang Won, Oh, Juhyun, Oh, Hyun-Kyung, Lee, Jae-Hyun, Zheng, Hui, Castro, Cesar M., Yoo, Yeong-Eun, Kim, Min-Gon, Cheon, Jinwoo, Weissleder, Ralph, Lee, Hakho

المصدر: Science Translational Medicine; 10/20/2021, Vol. 13 Issue 616, p1-10, 10p

مصطلحات موضوعية: SALIVA, MARIJUANA, TETRAHYDROCANNABINOL, COGNITIVE ability, CLINICAL drug trials, DRUG use testing

مستخلص: keyimage.jpg Quick testing: Several tests have been developed to detect tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, from biological samples. However, current methods have low sensitivity and generally require relatively long time. Now, Yu et al. developed a rapid assay able to detect THC with high sensitivity in minutes from oral fluid. The method, called express probe for on-site cannabis inhalation or EPOCH, was tested in marijuana users and controls. EPOCH was able to detect THC with high sensitivity (compatible with regulatory guidelines) and provided results within 5 min. The half-life of THC in oral fluid was reported to be 1.4 hours. The results demonstrate efficacy and convenience of using EPOCH to monitor THC on site from oral fluids. Tetrahydrocannabinol (THC), the primary psychoactive ingredient of cannabis, impairs cognitive and motor function in a concentration-dependent fashion. Drug testing is commonly performed for employment and law enforcement purposes; however, available tests produce low-sensitive binary results (lateral flow assays) or have long turnaround (gas chromatography–mass spectrometry). To enable on-site THC quantification in minutes, we developed a rapid assay for oral THC analysis called EPOCH (express probe for on-site cannabis inhalation). EPOCH features distinctive sensor design such as a radial membrane and transmission optics, all contained in a compact cartridge. This integrated approach permitted assay completion within 5 min with a detection limit of 0.17 ng/ml THC, which is below the regulatory guideline (1 ng/ml). As a proof of concept for field testing, we applied EPOCH to assess oral fluid samples from cannabis users (n = 43) and controls (n = 43). EPOCH detected oral THC in all specimens from cannabis smokers (median concentration, 478 ng/ml) and THC-infused food consumers. Longitudinal monitoring showed a fast drop in THC concentrations within the first 6 hours of cannabis smoking (half-life, 1.4 hours). [ABSTRACT FROM AUTHOR]

: Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Leung, Hui Min, Birket, Susan E., Hyun, Chulho, Ford, Timothy N., Cui, Dongyao, Solomon, George M., Shei, Ren-Jay, Adewale, Adegboyega Timothy, Lenzie, Andrew R., Fernandez-Petty, Courtney M., Zheng, Hui, Palermo, Justin H., Cho, Do-Yeon, Woodworth, Bradford A., Yonker, Lael M., Hurley, Bryan P., Rowe, Steven M., Tearney, Guillermo J.

المصدر: Science Translational Medicine; 8/7/2019, Vol. 11 Issue 504, p1-12, 12p

مصطلحات موضوعية: CYSTIC fibrosis, MUCOCILIARY system, TOMOGRAPHY, GENETIC disorders, ION transport (Biology), OPTICAL coherence tomography, OPTICAL tomography, EPITHELIAL cells

مستخلص: Mucociliary microscopy: Epithelial ion transport is dysfunctional in individuals with cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator that results in increased mucus accumulation, infection, and loss of lung function. Leung et al. developed an intranasal optical imaging probe with subcellular resolution that detected alterations in airway mucociliary transport in individuals with CF. Along with increased reflectivity in mucus and thicker mucus layers, the authors found areas of the epithelium lacking cilia, thinning of the periciliary liquid layer, and delayed mucociliary transport rate. Results suggest that intranasal micro-optical coherence tomography could help monitor disease status in individuals with respiratory conditions. Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-μm resolution micro-optical coherence tomography (μOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by μOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of μOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance. [ABSTRACT FROM AUTHOR]

: Copyright of Science Translational Medicine is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)