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In Situ Labeling of Pathogenic Tau Using Photo-Affinity Chemical Probes

ACS CHEMICAL BIOLOGY 2025年第3期20卷 581-591页

作者： Nie, Pengju Wu, You Robinson, John Mekala, Shekar Lee, Virginia M. Y. Li, Yue-Ming Mem Sloan Kettering Canc Ctr Chem Biol Program New York NY 10065 USA Mem Sloan Kettering Canc Ctr Triinst PhD Program Chem Biol New York NY 10065 USA Univ Penn Inst Aging Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Ctr Neurodegenerat Dis Res Perelman Sch Med Philadelphia PA 19104 USA

Tau aggregation plays a crucial role in the development of Alzheimer's disease (AD). Developing specific techniques that can isolate pathogenic tau from brain tissue is important for understanding tauopathies and advancing targeted therapies. Here, we develop photoaffinity small molecular probes and a novel method for in situ tissue labeling and investigate their activity in interacting with tau in cells and AD patient brains. Based on the reported chemical structures of tau PET tracers, we designed and synthesized two tau-specific probes, namely, Tau-2 and Tau-4. After validation in cell, mouse model, and patient brain samples, our photolabeling results suggested that Tau-2 effectively labels soluble tau in cell and mouse models, while Tau-4 selectively binds high-molecular-weight tau aggregates in late-stage AD patient brain tissues. Proteomic analysis verified the specific isolation of pathogenic tau from AD brain samples. Collectively, these findings underscore the potential of our photoaffinity probes as powerful tools for investigating tau proteins and neurofibrillary tangles in neurodegenerative diseases.

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A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains

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NATURE GENETICS 2023年第12期55卷 2104-+页

作者： Sziraki, Andras Lu, Ziyu Lee, Jasper Banyai, Gabor Anderson, Sonya Abdulraouf, Abdulraouf Metzner, Eli Liao, Andrew Banfelder, Jason Epstein, Alexander Schaefer, Chloe Xu, Zihan Zhang, Zehao Gan, Li Nelson, Peter T. Zhou, Wei Cao, Junyue Rockefeller Univ Lab Single Cell Genom & Populat Dynam New York NY 10021 USA Rockefeller Univ David Rockefeller Grad Program Biosci New York NY 10021 USA Univ Kentucky Dept Pathol Lexington KY USA Univ Kentucky Sanders Brown Ctr Aging Lexington KY 40536 USA Triinst MD PhD Program New York NY USA Triinst PhD Program Computat Biol & Med New York NY USA Rockefeller Univ High Performance Comp Resource Ctr New York NY 10021 USA Weill Cornell Med Helen & Robert Appel Alzheimers Dis Res Inst New York NY USA

Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer's disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer's pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.

关键词： Alzheimer's disease Transcriptomics

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A Multidimensional Typology of Religiosity in Three-Generation Families

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PSYCHOLOGY OF RELIGION AND SPIRITUALITY 2024年第2期16卷 142-150页

作者： Hwang, Woosang Yoon, Joonsik Brown, Maria T. Silverstein, Merril Syracuse Univ Aging Studies Inst 310A Lyman Hall Syracuse NY 13244 USA Syracuse Univ Social Sci PhD Program Syracuse NY 13244 USA Syracuse Univ Dept Human Dev & Family Sci Syracuse NY 13244 USA Syracuse Univ Dept Sociol Syracuse NY 13244 USA

There is broad consensus that religiosity is multidimensional in nature, but little is known regarding how religiosity profiles are similar or different across grandparent, parent, and grandchild generations. In this investigation, we aim to identify religious typologies among grandparents, parents, and grandchildren in a multigenerational sample, and describe similarities in typologies across generations. Data derived from the 2005 wave of the Longitudinal Study of Generation. To address the first aim, latent class analysis and multiple-group latent class analysis were conducted based on 411 grandparents, 705 parents, and 610 grandchildren. To address the second aim, latent transition analysis was conducted based on 216 grandparent-parent-grandchild triads. Results of the latent class analysis showed that same four-class religious typology was identified in three generations: strongly religious, weakly religious, personally religious, and doctrinally religious. In addition, results of latent transition analysis showed that strongly and weakly religious types are more likely to be repeated from grandparent to grandchild generations, compared to personally and doctrinally religious types. Our findings complement previous studies that religiosity is a multidimensional construct and that religiosity class membership at the extremes is largely invariant across three generations. Also, our findings indicate that the two intermediate religious typologies (personally and doctrinally religious) are not as intergenerationally stable as strongly and weakly religious types.

关键词： religiosity intergenerational correspondence grandparent-parent-grandchild triad spiritual but not religious

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Multidimensional sleep health is associated with physical frailty in a national sample of Taiwanese community-dwelling older adults: Sex matters

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SLEEP HEALTH 2022年第5期8卷 528-535页

作者： Chen, Tuo-Yu Lee, Soomi Buxton, Orfeu M. Taipei Med Univ Coll Publ Hlth PhD Program Global Hlth & Hlth Secur Taipei City 110 Taiwan Univ S Florida Sch Aging Studies 4202 East Fowler AveMHC 1344 Tampa FL USA Penn State Univ Dept Biobehav Hlth University Pk PA USA Taipei Med Univ Coll Publ Hlth PhD Program Global Hlth & Hlth Secur 250 Wuxing St Taipei City 110 Taiwan

Objectives: Although individual sleep characteristics are related to frailty, these characteristics do not occur separately. A multidimensional measure of sleep might provide a better estimation of frailty compared to isolated sleep characteristics. This study investigated the association of a multidimensional measure of sleep health with frailty both across and within sex groups. Design: Data were from the Taiwan Longitudinal Study on aging (2011), a survey with a nationally representative sample of Taiwanese older adults (N = 2,015). Frailty was defined using the Fried criteria. Self-reported sleep during the past month was used to conceptualize the five sleep health dimensions in the SATED model. Their relationship was estimated using logistic regression analysis adjusting for sociodemographic characteristics (age, sex, education), health status (comorbidity, cognitive function, pain, depressive symptoms [excluding items overlapping with frailty and sleep]), and health risk behaviors (drinking, smoking, lack of Results: Having a better sleep health composite score was significantly related to lower odds of being frail in both sexes adjusting for sociodemographic characteristics. This association remained significant among women but not among men after adding health and risk behaviors to the models. Satisfaction and alertness in both sexes and duration among women were significantly associated with frailty adjusting for sociodemographic characteristics. Only alertness among men was significantly related to frailty in the model with all covariates. Conclusions: Our findings show that having better sleep health across multiple dimensions is related to a lower risk of being frail, with differential risks for women and men. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of National Sleep Foundation. This is an open access article under the CC BY-NC-ND license (http://***/licenses/by-nc-nd/4.0/)

关键词： Sleep health Frailty Sex Older adults

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The mediating role of nurses' attitude towards reporting child abuse and neglect

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JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES 2024年 78卷 106-111页

作者： Zusman, Nurit Koton, Silvia Tabak, Nili Wruble, Anna C. Kienski Woloski Henrietta Szold Sch Nursing Hadassah Jerusalem Israel Hebrew Univ Jerusalem Fac Med Jerusalem Israel Henrietta Szold Hadassah Hebrew Univ Fac Med Sch Nursing Res HUJI Jerusalem Israel Tel Aviv Univ Herczeg Inst Aging Tel Aviv Israel Sackler Fac Med Sch Hlth Profess Dept Nursing PhD Program IL-6997801 Tel Aviv Israel Tel Aviv Univ Nursing Dept Tel Aviv Israel

Purpose: Attitudes towards reporting child abuse and neglect play a significant role in determining the tendency to report abuse and neglect. In addition, Cognitive Response Theory (Shen, 2020) suggests that individuals actively process messages by producing pro and/or counter arguments referred to as "Gain - loss thoughts". However, literature positioning the variable, attitudes towards reporting, as a mediator, as well as its importance, are limited. The purpose of the study was to investigate the mediating effect of pediatric nurses' attitudes between "gain-loss thoughts" and the tendency to report child abuse and neglect. Design and methods: A cross-sectional study examined 124 pediatric nurses working in central Israel's hospital departments concerning nurses' tendency to report (tendency to report = TTR), attitudes towards reporting, and "gain-loss thoughts" (positive and negative consequences for the child). Results: Most of the nurses had professional experience of 11 years or more (n = 75;62.5%). According to the findings, nurses' attitudes towards reporting mediate the effect of gain-loss on the TTR child abuse and neglect. Conclusions: Findings from this study contributed to our understanding of the importance of pediatric nurses' attitudes in determining the TTR abuse and neglect. Only nurses' positive attitudes towards reporting child abuse had a mediating effect on TTR. Practice implications: Understanding the importance of attitudes and gain-loss thoughts can serve as a strategy for training programs and in the assimilation of reporting obligations by health professionals in general and nurses in particular. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Attitude Child abuse Nursing report

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Rationale and design of a randomized controlled trial evaluating the effects of blueberry consumption versus placebo on brain health in older adults

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CONTEMPORARY CLINICAL TRIALS 2025年 154卷 107926-107926页

作者： Uttke, Zachary Gabriel, Olivia Smith, Ceilidh Guardino, Eric T. Mukamal, Kenneth Djousse, Luc Greater Boston Med Student Aging Res Boston MA USA Brown Univ MD PhD Program Providence RI USA Univ Texas Hlth San Antonio STX MSTP San Antonio TX USA Brigham & Womens Hosp Boston MA USA Beth Israel Deaconess Med Ctr Boston MA USA Harvard Med Sch Boston MA USA Harvard TH Chan Sch Publ Hlth Boston MA USA

Background: Age-related cognitive decline results in significant clinical and public health costs. Cognitive decline predisposes individuals to dementia and leads to difficulties with activities of daily living and increased hospitalizations. While a few dietary interventions have shown considerable promise at delaying cognitive decline, studies of the effects of long-term blueberry consumption on brain health among older adults have been limited and equivocal. Objective: To test the hypothesis that a 24-week intervention with blueberry powder versus placebo will improve (i) plasma biomarkers of brain health and (ii) cognitive performance in older adults. Methods: This randomized, double-blind, placebo-controlled trial will be conducted in older Americans aged 65-99 years old. Sixty-seven participants will be randomly assigned to receive either blueberry powder (20 g/d-equivalent of one (1) cup of fresh blueberries) or a placebo powder (20 g/d) for 24 weeks. Participants will undergo four clinic visits (baseline and 8 weeks, 16 weeks, and 24 weeks after randomization) for cognitive assessments, blood pressure measurements, and blood sample collections. Primary outcomes will be plasma levels of neurofilament light chain (NFL) and phosphorylated tau protein (pTau-181). Secondary outcomes will be plasma levels of glial fibrillary acidic protein (GFAP) and non-esterified fatty acids (NEFA);blood pressure during visits;and cognitive function. Conclusion: Findings from this trial will answer the question whether a long-term intervention with blueberry powder can improve (i) plasma biomarkers of brain health and (ii) cognitive function in older adults.

关键词： Blueberries Biomarkers Cognitive function Older adults Clinical trial

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Excitatory-inhibitory synaptic imbalance induced by acute intra-hippocampus injections of amyloid-β oligomers

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2025年 742卷 151133页

作者： Arriagada, Jorge Merceron, Daymara Ardiles, Alvaro Munoz, Pablo Paula-Lima, Andrea Univ Chile PhD Program Biomed Sci Santiago Chile Univ Valparaiso Ctr Translat Res Neuropharmacol CITNE Valparaiso Chile Univ Valparaiso Fac Med Med Sch Dept Pathol & Physiol Valparaiso Chile Univ Valparaiso Interuniv Ctr Hlth Aging CIES Valparaiso Chile Univ Chile Inst Res Dent Sci Fac Dent Santiago Chile Univ Chile Biomed Neurosci Inst BNI Fac Med Santiago Chile Univ Chile Fac Med Dept Neurosci Santiago Chile

Alzheimer's disease (AD) is characterized by the accumulation of soluble amyloid-beta oligomers (A beta Os) in the brain, which disrupt synaptic function and promote cognitive decline. Here, we investigated the effects of A beta Os on excitatory and inhibitory synaptic transmission and plasticity by performing stereotaxic injections of A beta Os directly into the hippocampal CA1 region, followed by hippocampal slice isolation for electrophysiological measurements. A beta Os injections altered basal excitatory synaptic transmission, reducing field excitatory postsynaptic potentials (fEPSPs) and impairing excitatory long-term potentiation (LTP). Additionally, A beta Os injections significantly increased basal inhibitory synaptic transmission, as evidenced by the increased amplitude of field inhibitory postsynaptic potentials (fIPSPs), but impaired the induction and maintenance of inhibitory long-term potentiation (iLTP). Accordingly, we propose that A beta Os injections induce the saturation of the GABAergic system and thus disrupt the hippocampal excitatory-inhibitory balance. These findings highlight the dual impact of A beta Os on both excitatory and inhibitory synapses, generating synaptic dysregulation and possibly worsening cognitive decline in AD. Understanding these mechanisms could provide new insights for developing therapies to restore synaptic balance and hippocampal function in AD.

关键词： Alzheimer's disease Rat hippocampal slices Electrophysiology Synaptic transmission Immunofluorescence

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Religiosity and Mental Health Among Young-Adults in Generation X from Emerging to Established Adulthood

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JOURNAL OF ADULT DEVELOPMENT 2023年第1期30卷 108-117页

作者： Hwang, Woosang Cheng, Kent Jason Kim, Jeung Hyun Brown, Maria T. Vasilenko, Sara A. Silverstein, Merril Syracuse Univ Aging Studies Inst 307B Lyman Hall Syracuse NY 13244 USA Syracuse Univ Social Sci PhD Program Syracuse NY USA Syracuse Univ Dept Sociol Syracuse NY USA Syracuse Univ Sch Social Work Syracuse NY USA Syracuse Univ Dept Human Dev & Family Sci Syracuse NY USA

This investigation examined how religiosity in the period of life ranging from emerging to established adulthood is associated with mental health. To address this issue, we examined the relationship between multiple dimensions of religiosity among young-adult Gen-Xers and mental health (psychological well-being, depression, and self-esteem) over this important stage of adulthood. We selected 510 young-adults participating in the Longitudinal Study of Generations surveyed in 2000 (18-29 years), 2005 (23-34 years), and 2016 (34-45 years). Latent class analysis identified three latent religious classes across the three waves: nonreligious, strongly religious, and spiritual-but-not-religious. Young-adult Gen-Xers in the strongly religious class across the three measurements generally reported better mental health when they reached established adulthood than those in the nonreligious class. Mental health in established adulthood was not significantly different between strongly religious and spiritual-but-not-religious individuals. Findings suggest that religiosity may serve as an important resource for mental health in the transition to established adulthood. Implications are discussed in the context of declining religiosity in the US over recent decades.

关键词： Generation X Religiosity Spiritual-but-not-religious Mental health Emerging adulthood Established adulthood

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Caffeic acid phenethyl ester suppresses the expression of androgen receptor variant 7 via inhibition of CDK1 and AKT

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Cancer Gene Therapy 2024年第6期31卷 807-815页

作者： Kuo, Ying-Yu Huo, Chieh Li, Chia-Yang Chuu, Chih-Pin Institute of Cellular and System Medicine National Health Research Institutes Miaoli County Taiwan Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan Department of Medical Research Kaohsiung Medical University Kaohsiung Taiwan PhD Program for Aging and Graduate Institute of Basic Medical Science China Medical University Taichung City Taiwan Biotechnology Center National Chung Hsing University Taichung City Taiwan Department of Life Sciences National Central University Taoyuan City Taiwan

Androgen receptor (AR) splice variant 7 (AR-V7) is capable to enter nucleus and activate downstream signaling without ligand. AR-V7 assists the tumor growth, cancer metastasis, cancer stemness, and the evolvement of therapy-resistant prostate cancer (PCa). We discovered that caffeic acid phenethyl ester (CAPE) can repress the expression and downstream signaling of AR-V7 in PCa cells. CAPE blocked the gene transcription, nuclear localization, and protein abundance of AR-V7. CAPE inhibited the expression of U2AF65, SF2 and hnRNPF, which were splicing factors for AR-V7 intron. Additionally, CAPE decreased protein stability of AR-V7 and enhanced the proteosome-degradation of AR-V7. We observed that CDK1 and AKT regulated the expression and stability of AR-V7 via phosphorylation of Ser81 and Ser213, respectively. CAPE decreased the expression of CDK1 and AKT. Overexpression of CDK1 restored the abundance of AR-V7 in CAPE-treated PCa cells. Overexpression of AR-V7, AKT or CDK1 rescued the proliferation of PCa cells under CAPE treatment. Intraperitoneal injection of 10 mg/kg CAPE retarded the growth of 22Rv1 xenografts in nude mice and suppressed the protein levels of AR-V7, CDK1 and AKT in 22Rv1 xenografts. Our study provided the rationale of applying CAPE for inhibition of AR-V7 in prostate tumors. (Figure presented.). © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

关键词： Drug development Prostate cancer

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Adult hippocampal neurogenesis and social behavioural deficits in the R451C Neuroligin3 mouse model of autism are reverted by the antidepressant fluoxetine

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JOURNAL OF NEUROCHEMISTRY 2023年第3期165卷 318-333页

作者： Gioia, Roberta Seri, Tommaso Diamanti, Tamara Fimmano, Stefania Vitale, Marina Ahlenius, Henrik Kokaia, Zaal Tirone, Felice Micheli, Laura Biagioni, Stefano Lupo, Giuseppe Rinaldi, Arianna De Jaco, Antonella Cacci, Emanuele Sapienza Univ Rome Dept Biol & Biotechnol Charles Darwin Rome Italy Sapienza Univ Rome PhD Program Behav Neurosci Rome Italy Lund Univ Fac Med Dept Clin Sci Lund Neurol Stem Cells Aging & Neur Lund Sweden Lund Stem Cell Ctr Lund Sweden Lund Univ Hosp Lund Stem Cell Ctr Dept Clin Sci Lund Sweden CNR Inst Biochem & Cell Biol Rome Italy Sapienza Univ Rome Ctr Res Neurobiol D Bovet Rome Italy

Neuron generation persists throughout life in the hippocampus but is altered in animal models of neurological and neuropsychiatric diseases, suggesting that disease-associated decline in cognitive and emotional hippocampal-dependent behaviours might be functionally linked with dysregulation of postnatal neurogenesis. Depletion of the adult neural stem/progenitor cell (NSPCs) pool and neurogenic decline have been recently described in mice expressing synaptic susceptibility genes associated with autism spectrum disorder (ASDs). To gain further insight into mechanisms regulating neurogenesis in mice carrying mutations in synaptic genes related to monogenic ASDs, we used the R451C Neuroligin3 knock-in (Nlgn3 KI) mouse, which is characterized by structural brain abnormalities, deficits in synaptic functions and reduced sociability. We show that the number of adult-born neurons, but not the size of the NSPC pool, was reduced in the ventral dentate gyrus in knock-in mice. Notably, this neurogenic decline was rescued by daily injecting mice with 10 mg/Kg of the antidepressant fluoxetine for 20 consecutive days. Sustained treatment also improved KI mice's sociability and increased the number of c-Fos active adult-born neurons, compared with vehicle-injected KI mice. Our study uncovers neurogenesis-mediated alterations in the brain of R451C KI mouse, showing that the R451C Nlgn3 mutation leads to lasting, albeit pharmacologically reversible, changes in the brain, affecting neuron formation in the adult hippocampus. Our results suggest that fluoxetine can ameliorate social behaviour in KI mice, at least in part, by rescuing adult hippocampal neurogenesis, which may be relevant for the pharmacological treatment of ASDs.

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