Molecular Psychiatry最新文献

{"title":"Prefrontal parvalbumin interneurons mediate CRHR1-dependent early-life stress-induced cognitive deficits in adolescent male mice","authors":"Yu-Nu Ma, Chao-Juan Yang, Chen-Chen Zhang, Ya-Xin Sun, Xing-Duo Yao, Xiao Liu, Xue-Xin Li, Hong-Li Wang, Han Wang, Ting Wang, Xiao-Dong Wang, Chen Zhang, Yun-Ai Su, Ji-Tao Li, Tian-Mei Si","doi":"10.1038/s41380-024-02845-6","DOIUrl":"https://doi.org/10.1038/s41380-024-02845-6","url":null,"abstract":"<p>Cognitive impairment, a core symptom of psychiatric disorders, is frequently observed in adolescents exposed to early-life stress (ES). However, the underlying neural mechanisms are unclear, and therapeutic efficacy is limited. Targeting parvalbumin-expressing interneurons (PVIs) in the medial prefrontal cortex (mPFC), we report that ES reduces mPFC PVI activity, which causally mediated ES-induced cognitive deficits in adolescent male mice through chemogenetic and optogenetic experiments. To understand the possible causes of PVI activity reduction following ES, we then demonstrated that ES upregulated corticotropin-releasing hormone (CRH) receptor 1 [CRHR1, mainly expressed in pyramidal neurons (PNs)] and reduced activity of local pyramidal neurons (PNs) and their excitatory inputs to PVIs. The subsequent genetic manipulation experiments (CRHR1 knockout, CRH overexpression, and chemogenetics) highlight that ES-induced PVI activity reduction may result from CRHR1 upregulation and PN activity downregulation and that PVIs play indispensable roles in CRHR1- or PN-mediated cognitive deficits induced by ES. These results suggest that ES-induced cognitive deficits could be attributed to the prefrontal CRHR1-PN-PVI pathway. Finally, treatment with antalarmin (a CRHR1 antagonist) and environmental enrichment successfully restored the PVI activity and cognitive deficits induced by ES. These findings reveal the neurobiological mechanisms underlying ES-induced cognitive deficits in adolescent male mice and highlight the therapeutic potentials of PVIs in stress-related cognitive deficits in adolescent individuals.</p><figure></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"181 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of neuropilin-2 expression in inhibitory neurons impairs hippocampal circuit development and enhances risk for autism-related behaviors and seizures","authors":"Deepak Subramanian, Carol Eisenberg, Andrew Huang, Jiyeon Baek, Haniya Naveed, Samiksha Komatireddy, Michael W. Shiflett, Tracy S. Tran, Vijayalakshmi Santhakumar","doi":"10.1038/s41380-024-02839-4","DOIUrl":"https://doi.org/10.1038/s41380-024-02839-4","url":null,"abstract":"<p>Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"3 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal immune origins of brain aging differ by sex","authors":"Jill M. Goldstein, Kyoko Konishi, Sarah Aroner, Hang Lee, Anne Remington, Tanuja Chitnis, Stephen L. Buka, Mady Hornig, Stuart A. Tobet","doi":"10.1038/s41380-024-02798-w","DOIUrl":"https://doi.org/10.1038/s41380-024-02798-w","url":null,"abstract":"<p>With an increasing aging population and Alzheimer’s disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention. Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience. There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways. Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring’s memory and immune function that will be retained across the lifespan. Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50). Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later. In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife. Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance. Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"13 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dopaminergic basis of negative symptoms in schizophrenia: an addendum","authors":"Ana Weidenauer, Irena Dajic, Nicole Praschak-Rieder, Matthäus Willeit","doi":"10.1038/s41380-024-02828-7","DOIUrl":"https://doi.org/10.1038/s41380-024-02828-7","url":null,"abstract":"<p>We would like to address the results of two recent positron emission tomography (PET) imaging studies and discuss them in relation to our own findings [1]. The first study we would like to refer to is an [¹⁸F]FDOPA PET investigation performed in two independent cohorts of drug-free patients with schizophrenia [2]. [¹⁸F]FDOPA is a direct precursor of dopamine, and its uptake is generally assumed to reflect presynaptic dopamine synthesis and storage capacity. In contrast to earlier [¹⁸F]FDOPA PET studies, Eisenberg et al. failed to find elevated [¹⁸F]FDOPA uptake in patients with schizophrenia. However, the study observed inverse correlations between [¹⁸F]FDOPA uptake rates into the putamen and severity of negative symptoms in both cohorts. Thus, the Eisenberg et al. findings indicate that reduced dopamine transmission in the putamen may be an important element in the formation of negative symptoms of schizophrenia.</p><p>The second study we would like to address [3] presents the results of a PET study on the effects of oral methylphenidate (MPH) administration on non-displaceable binding potential (BP_ND) values of the dopamine D_2/3 receptor agonist radioligand [¹¹C]-(+)-PHNO in individuals at clinical high-risk (CHR) for psychosis. Changes in radioligand binding to dopamine D_2/3 receptors after a pharmacological or behavioral challenge provide an indirect measure for the fluctuations in extracellular dopamine levels. The authors aimed to replicate and extend findings on alterations in subcortical availability of dopamine in CHR individuals, as previous studies have shown that subcortical dopamine functioning is elevated in full-blown psychosis, and that enhanced dopamine transmission might be present even before psychosis onset [4, 5]. This, however, was questioned by a more recent meta-analysis [6]. The main finding of the study by Girgis et al. [3] was that, compared to non-CHR controls, CHR subjects showed greater changes in [¹¹C]-(+)-PHNO BP_ND values (∆BP_ND) in response to the MPH challenge. This conforms well with results from earlier challenge-studies in patients with schizophrenia [1, 4, 7,8,9,10,11] and extends the use of this method towards prodromal stages of psychosis (which, of course, can only be termed as such in retrospect). In addition, the study by Girgis et al. observed an inverse relationship between the expression of negative symptoms and [¹¹C]-(+)-PHNO ∆BP_ND in the ventral striatum of CHR subjects.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"63 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining antipsychotic treatment strategies in schizophrenia: discovery of genetic biomarkers for enhanced drug response prediction","authors":"Luan Chen, Cong Huai, Chuanfu Song, Shaochang Wu, Yong Xu, Zhenghui Yi, Jinsong Tang, Lingzi Fan, Xuming Wu, Zhenhua Ge, Chuanxin Liu, Deguo Jiang, Saizheng Weng, Guoqiang Wang, Xinfeng Zhang, Xudong Zhao, Lu Shen, Na Zhang, Hao Wu, Yongzhi Wang, Zhenglin Guo, Suli Zhang, Bixuan Jiang, Wei Zhou, Jingsong Ma, Mo Li, Yunpeng Chu, Chenxi Zhou, Qinyu Lv, Qingqing Xu, Wenli Zhu, Yan Zhang, Weibin Lian, Sha Liu, Xinrong Li, Songyin Gao, Aihong Liu, Lei He, Zhenzhen Yang, Bojian Dai, Jiaen Ye, Ruiqian Lin, Yana Lu, Qi Yan, Yalan Hu, Qinghe Xing, Hailiang Huang, Shengying Qin","doi":"10.1038/s41380-024-02841-w","DOIUrl":"https://doi.org/10.1038/s41380-024-02841-w","url":null,"abstract":"<p>Schizophrenia (SCZ) is a severe mental disorder affecting around 1% of individuals worldwide. The variability in response to antipsychotic drugs (APDs) among SCZ patients presents a significant challenge for clinicians in determining the most effective medication. In this study, we investigated the biological markers and established a predictive model for APD response based on a large-scale genome-wide association study using 3269 Chinese schizophrenia patients. Each participant underwent an 8-week treatment regimen with one of five mono-APDs: olanzapine, risperidone, aripiprazole, quetiapine, or amisulpride. By dividing the response into ordinal groups of “high”, “medium”, and “low”, we mitigated the bias of unclear treatment outcome and identified three novel significantly associated genetic loci in or near <i>CDH12</i>, <i>WDR11</i>, and <i>ELAVL2</i>. Additionally, we developed predictive models of response to each specific APDs, with accuracies ranging from 79.5% to 98.0%. In sum, we established an effective method to predict schizophrenia patients’ response to APDs across three categories, integrating novel biomarkers to guide personalized medicine strategies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"99 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale proteomic analyses of incident Alzheimer’s disease reveal new pathophysiological insights and potential therapeutic targets","authors":"Yi Zhang, Yu Guo, Yu He, Jia You, YaRu Zhang, LinBo Wang, ShiDong Chen, XiaoYu He, Liu Yang, YuYuan Huang, JuJiao Kang, YiJun Ge, Qiang Dong, JianFeng Feng, Wei Cheng, JinTai Yu","doi":"10.1038/s41380-024-02840-x","DOIUrl":"https://doi.org/10.1038/s41380-024-02840-x","url":null,"abstract":"<p>Pathophysiological evolutions in early-stage Alzheimer’s disease (AD) are not well understood. We used data of 2923 Olink plasma proteins from 51,296 non-demented middle-aged adults. During a follow-up of 15 years, 689 incident AD cases occurred. Cox-proportional hazard models were applied to identify AD-associated proteins in different time intervals. Through linking to protein categories, changing sequences of protein z-scores can reflect pathophysiological evolutions. Mendelian randomization using blood protein quantitative loci data provided causal evidence for potentially druggable proteins. We identified 48 AD-related proteins, with CEND1, GFAP, NEFL, and SYT1 being top hits in both near-term (HR:1.15–1.77; <i>P</i>:9.11 × 10⁻⁶⁵–2.78 × 10⁻⁶) and long-term AD risk (HR:1.20-1.54; <i>P</i>:2.43 × 10⁻²¹–3.95 × 10⁻⁶). These four proteins increased 15 years before AD diagnosis and progressively escalated, indicating early and sustained dysfunction in synapse and neurons. Proteins related to extracellular matrix organization, apoptosis, innate immunity, coagulation, and lipid homeostasis showed early disturbances, followed by malfunctions in metabolism, adaptive immunity, and final synaptic and neuronal loss. Combining CEND1, GFAP, NEFL, and SYT1 with demographics generated desirable predictions for 10-year (AUC = 0.901) and over-10-year AD (AUC = 0.864), comparable to full model. Mendelian randomization supports potential genetic link between CEND1, SYT1, and AD as outcome. Our findings highlight the importance of exploring the pathophysiological evolutions in early stages of AD, which is essential for the development of early biomarkers and precision therapeutics.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"6 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive functioning in people with psychotic experiences: a systematic review and meta-analysis study.","authors":"Ryan Sai Ting Chu, Ivan Wai Lok Chu, Esther Wing-Chi Yip, Joe Kwun Nam Chan, Corine Sau Man Wong, Christy Lai-Ming Hui, Eric Yu Hai Chen, Sherry Kit Wa Chan, Edwin Ho Ming Lee, Simon Sai Yu Lui, Wing Chung Chang","doi":"10.1038/s41380-024-02823-y","DOIUrl":"10.1038/s41380-024-02823-y","url":null,"abstract":"<p><p>Earlier research suggested that psychotic experiences (PEs), the extended-psychosis phenotype, are associated with cognitive impairment. Recent studies, however, revealed more mixed findings, and patterns and magnitude of cognitive deficits in PEs remain uncertain. We aimed to systematically review and quantitatively synthesize estimates of cognitive functioning covering a wide array of domains in individuals with versus without PEs. We systematically searched four databases from inception to 6 July 2023. We generated pooled effect size (Hedges'g) using random-effects models. Subgroup analyses and meta-regression examining the moderating effect of sex, age at PE assessment, study design, cognitive task, and PE assessment instrument on cognitive functioning were performed when applicable. The study was registered with PROSPERO (CRD42023442528). Twenty-seven and six studies were included for meta-analysis of cognitive functioning comparing individuals with versus without PEs (n = 82,561; 10,251 individuals with PEs) and individuals with high-level versus low-level PEs (n = 8062; 813 individuals with high-level PEs), respectively. Individuals with PEs exhibited worse cognitive performance in general cognition (Hedges'g = -0.10 [95%CI = -0.18 to -0.02]), verbal fluency (Hedges'g = -0.05 [95%CI = -0.10 to -0.00]), visual memory (Hedges'g = -0.21 [95%CI = -0.38 to -0.03]), and working memory (Hedges'g = -0.16 [95%CI = -0.28 to -0.04]). Meta-regression revealed that general cognition associated with PEs was related to younger age (z = 3.37, p = 0.001), male sex (z = -2.59, p = 0.010), and cognitive assessment before PE assessment (z = -2.15, p = 0.031), whereas working memory in individuals with PEs was associated with concurrent cognitive and PE assessment (z = 6.19, p < 0.001). We failed to find moderating effect of the choice of PE assessment instrument or cognitive task on cognitive functioning in PEs. Additional analysis showed no significant difference in the performance of any cognitive domains between individuals with high-level versus low-level PEs. Limitations included studies primarily derived from Western countries, no social-cognitive domains, and varied PE measurement. In sum, PEs are associated with milder and more circumscribed cognitive impairment relative to psychotic disorders. Future research is required to clarify differential cognitive trajectories between individuals with transient PEs and persistent/recurrent-PEs.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating genome-wide information and wearable device data to explore the link of anxiety and antidepressants with pulse rate variability.","authors":"Eleni Friligkou, Dora Koller, Gita A Pathak, Edward J Miller, Rachel Lampert, Murray B Stein, Renato Polimanti","doi":"10.1038/s41380-024-02836-7","DOIUrl":"10.1038/s41380-024-02836-7","url":null,"abstract":"<p><p>This study explores the genetic and epidemiologic correlates of long-term photoplethysmography-derived pulse rate variability (PRV) measurements with anxiety disorders. Individuals with whole-genome sequencing, Fitbit, and electronic health record data (N = 920; 61,333 data points) were selected from the All of Us Research Program. Anxiety polygenic risk scores (PRS) were derived with PRS-CS after meta-analyzing anxiety genome-wide association studies from three major cohorts- UK Biobank, FinnGen, and the Million Veterans Program (N_Total =364,550). PRV was estimated as the standard deviation of average five-minute pulse wave intervals over full 24-hour pulse rate measurements (SDANN). Antidepressant exposure was defined as an active antidepressant prescription at the time of the PRV measurement in the EHR. Anxiety PRS and antidepressant use were tested for association with daily SDANN. The potential causal effect of anxiety on PRV was assessed with one-sample Mendelian randomization (MR). Anxiety PRS was independently associated with reduced SDANN (beta = -0.08; p = 0.003). Of the eight antidepressant medications and four classes tested, venlafaxine (beta = -0.12, p = 0.002) and bupropion (beta = -0.071, p = 0.01), tricyclic antidepressants (beta = -0.177, p = 0.0008), selective serotonin reuptake inhibitors (beta = -0.069; p = 0.0008) and serotonin and norepinephrine reuptake inhibitors (beta = -0.16; p = 2×10^-6) were associated with decreased SDANN. One-sample MR indicated an inverse effect of anxiety on SDANN (beta = -2.22, p = 0.03). Anxiety and antidepressants are independently associated with decreased PRV, and anxiety appears to exert a causal effect on reduced PRV. Those observational findings provide insights into the impact of anxiety on PRV.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pathogenic APP N-terminal Val225Ala mutation alters tau protein liquid-liquid phase separation and exacerbates synaptic damage.","authors":"Jiang Chen, Song Li, Fengning Zhang, Junsheng Chen, Chuanbin Cai, Yi Guo, Zhifeng Lei, Ling-Hui Zeng, Dan Zi, Yong Shen, Jun Tan","doi":"10.1038/s41380-024-02837-6","DOIUrl":"10.1038/s41380-024-02837-6","url":null,"abstract":"<p><p>Amyloid precursor protein (APP) is predominantly located in synapses of neurons and its mutations have been well recognized as the most important genetic causal factor for the familial Alzheimer's disease (AD). While most disease-causal mutations of APP occur within the Aβ-coding region or immediately proximal, the pathological impacts of mutations in the N-terminus of APP protein, which remote from the Aβ sequence, on neuron and synapse are still largely unknown. It was recently reported a pathogenic APP N-terminal Val225Ala mutation (APP_V225A) with clinically featuring progressive dementia and typical AD pathologies in brain. In our present study, we further found that APP_V225A mutation alters the N-terminal structure of APP, which enhances its binding affinity to tau protein and significantly increases APP-mediated endocytosis. Consequently, APP_V225A promotes the uptake of extracellular tau into SH-SY5Y cells, further linking the structural change in APP to intracellular tau accumulation. In addition, APP_V225A also notably alters the liquid-liquid phase separation (LLPS) of intracellular tau and intensified tau phosphorylation and aggregation in SH-SY5Y cells. Moreover, APP_V225A promote AD-like tau pathology and synaptic damages in human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells and neurons, as well as in hiPSCs-derived human brain organoids and mouse brain, which can be ameliorated by tau knockdown. Proximity labeling identified several key APP_V225A-interacting proteins, including HS3ST3A1, which was shown to directly regulate tau LLPS and phosphorylation. These findings nicely build on our previous work on roles for APP in tau-related pathological phenotypes and further highlight the involvement of N-terminal APP as the key region for both amyloidopathy and tauopathy, two aspects of AD pathogenesis and progression. Our study may also provide a theoretical breakthrough for AD therapy and highlight the important hub roles of APP and making previously neglected N-terminal APP as a potential target for the discovery of novel disease-modifying therapeutic agents against AD, holding significant scientific values and clinical promise.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal neurogenesis in adult primates: a systematic review.","authors":"Thomas Elliott, Kathy Y Liu, Jemma Hazan, Jack Wilson, Hemisha Vallipuram, Katherine Jones, Jansher Mahmood, Guy Gitlin-Leigh, Robert Howard","doi":"10.1038/s41380-024-02815-y","DOIUrl":"10.1038/s41380-024-02815-y","url":null,"abstract":"<p><p>It had long been considered that no new neurons are generated in the primate brain beyond birth, but recent studies have indicated that neurogenesis persists in various locations throughout the lifespan. The dentate gyrus of the hippocampus is of particular interest due to the postulated role played by neurogenesis in memory. However, studies investigating the presence of adult hippocampal neurogenesis (AHN) have reported contradictory findings, and no systematic review of the evidence has been conducted to date. We searched MEDLINE, Embase and PsycINFO on 27^th June 2023 for studies on hippocampal neurogenesis in adult primates, excluding review papers. Screening, quality assessment and data extraction was done by independent co-raters. We synthesised evidence from 112 relevant papers. We found robust evidence, primarily supported by immunohistochemical examination of tissue samples and neuroimaging, for newly generated neurons, first detected in the subgranular zone of the dentate gyrus, that mature over time and migrate to the granule cell layer, where they become functionally integrated with surrounding neuronal networks. AHN has been repeatedly observed in both humans and other primates and gradually diminishes with age. Transient increases in AHN are observed following acute insults such as stroke and epileptic seizures, and following electroconvulsive therapy, and AHN is diminished in neurodegenerative conditions. Markers of AHN correlate positively with measures of learning and short-term memory, but associations with antidepressant use and mood states are weaker. Heterogeneous outcome measures limited quantitative syntheses. Further research should better characterise the neuropsychological function of neurogenesis in healthy subjects.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}