Molecular Psychiatry最新文献

{"title":"Semaphorin 3A-mediated perineuronal nets formation incubates depressive-like behaviors in male mice via activating parvalbumin-expressing interneurons","authors":"Yuan-Xi Mei, Hong-Sheng Chen, Qun-Ling Cao, Wan-Wan Lv, Yang Liu, Si-Long Deng, Qigang Zhou, Zhang-Jin Zhang, Fang Wang, Zhuang-Li Hu, Jian-Guo Chen","doi":"10.1038/s41380-025-03239-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03239-y","url":null,"abstract":"<p>Dysfunction of parvalbumin-expressing interneurons (PV-INs) in the cerebral cortex has been implicated in major depressive disorder. Perineuronal nets (PNNs), which encapsulate PV-INs, are considered to influence the structural and functional properties of PV-INs. Semaphorin 3A (Sema3A) is a secreted protein constituent of PNNs, but the specific roles of Sema3A in modulating PV-INs during stress remain unknown. Here, we demonstrated that Sema3A, secreted by GABAergic interneurons, contributed to the response to chronic stress in male mice. The accumulation of Sema3A interacts with PNNs and facilitates PNNs wrapping of PV-INs, leading to a decrease in inhibitory synaptic input and an increase in the excitability of PV-INs. Sema3A-mediated formation of PNNs and the subsequent increase in PV-INs excitability may promote the development of depressive-like behaviors induced by stress. These results elucidate a molecular pathway in which Sema3A, a component of PNNs, dynamically governs the function of PV-INs to facilitate adaptive behavioral responses to stress.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"164 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025428","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":"Autophagy controls the hippocampal postsynaptic organization and affects cognition in a mouse model of Fragile X syndrome","authors":"Ziyan Zhang, Cameron Keyser, Yaxin Li, Breandan J. Rosolia, Morgan W. Porch, Wen Zhang, Bin Su, Peng Jiang, R. Suzanne Zukin, Jingqi Yan","doi":"10.1038/s41380-025-03207-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03207-6","url":null,"abstract":"<p>Dysregulated spine morphology is a common feature in the pathology of many neurodevelopmental and neuropsychiatric disorders. Overabundant immature dendritic spines in the hippocampus are causally related to cognitive deficits of Fragile X syndrome (FXS), the most common form of heritable intellectual disability. Recent findings from us and others indicate autophagy plays important roles in synaptic stability and morphology, and autophagy is downregulated in FXS neurons. However, the mechanism remains unclear. In this study, we identified that activated autophagy degrades the eukaryotic initiation factor 4G1 (eIF4G1) and postsynaptic density protein-95 (PSD-95) in hippocampal neurons of <i>Fmr1</i> KO mice and FXS neurons from patients, which subsequently corrected the dysregulated postsynaptic organization and actin assembly, the critical processes determining synaptic maturation and density. Centrally activating autophagy in hippocampus degrades eIF4G1 and PSD-95, restores actin dynamics, and improves cognition of <i>Fmr1</i> KO mice. In human neurons derived from patients diagnosed with both FXS and intellectual disability, activating autophagy corrected the aberrant actin assembly. Thus, our findings revealed a previously unappreciated mechanism through which autophagy affects actin assembly and synaptic organization, suggesting a critical role of autophagy in regulating structural synaptic plasticity in healthy and diseased conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025426","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":"Genetically modeled GLP1R and GIPR agonism reduce binge drinking and alcohol-associated phenotypes: a multi-ancestry drug-target Mendelian randomization study","authors":"Joshua Reitz, Daniel B. Rosoff, Tyler Perlstein, Alexandra Wagner, Jeesun Jung, Josephin Wagner, Benjamin C. Reiner, Falk W. Lohoff","doi":"10.1038/s41380-025-03199-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03199-3","url":null,"abstract":"<p>Pharmacological modulation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) through dual GIP/GLP-1 receptor agonists, commonly used for diabetes and obesity, shows promise in reducing alcohol consumption. We applied drug-target Mendelian randomization (MR) using genetic variation at these loci to assess their long-term effects on problematic alcohol use (PAU), binge drinking, alcohol misuse classifications, liver health, and other substance use behaviors. Genetic proxies for lowered BMI, modeling the appetite-suppressing and weight-reducing effects of variants in both the <i>GIPR</i> and <i>GLP1R</i> loci (“<i>GIPR/GLP1R</i>”), were linked with reduced binge drinking in the primary (β = −0.44, 95% CI [−0.72, −0.15], P = 2.42 × 10⁻³) and replication data (β = −0.13, [−0.22, −0.04], P = 0.0058). HbA1c lowering via <i>GIPR/GLP1R</i> variants was associated with reduced risk of heavy drinking with psychiatric comorbidities versus low-risk drinking (odds ratio [OR] = 0.62, [0.45, 0.85], P = 0.0031), with replication in independent HbA1c data (OR = 0.71, [0.60, 0.84], P = 5.22 × 10⁻⁵) and directional consistency with reduced PAU. Analysis of individual loci indicated that both <i>GIPR</i> and <i>GLP1R</i> were protective against heavy drinking, underscoring the importance of both targets. While estimates for other substance use disorders (tobacco, cannabis, opioid) were consistently null, food preference analyses revealed that BMI lowering via <i>GIPR/GLP1R</i> reduced fatty food liking (β = −1.58, [−2.01, −1.14], P = 1.62 × 10⁻¹²) and increased vegetarian food liking (β = 2.08, [1.17, 2.99], P = 8.22 × 10⁻⁶), implicating metabolic and appetite regulation pathways for the alcohol consumption findings. For liver health, HbA1c lowering via <i>GIPR/GLP1R</i> was associated with reduced NAFLD (β = −0.34, [−0.50, −0.18], P = 2.74 × 10⁻⁵) and lower ALT levels (β = −0.26, [−0.38, −0.15], P = 8.39 × 10⁻⁶), with replication supporting these findings. Consistency across multiple MR methods and colocalization analyses strengthened causal inference. Mediation analysis suggested reductions in hazardous alcohol consumption partially explain the cardioprotective effects of these agonists. Multi-ancestry analyses supported directionally aligned relationships in non-European cohorts. These findings support further clinical exploration of GLP1R, GIPR, and dual agonists in addiction medicine.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"15 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025427","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 mesocorticolimbic system in stimulant use disorder","authors":"Edythe D. London, Stephanie M. Groman, Marco Leyton, Harriet de Wit","doi":"10.1038/s41380-025-03148-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03148-0","url":null,"abstract":"<p>Stimulant Use Disorder (StUD) is a pervasive and extremely dangerous form of addiction for which there are currently no approved medications. Discovering treatments will require a deep understanding of the neural mechanisms underlying the behavioral effects of stimulant drugs. A major target is the mesocorticolimbic system. Individual differences in mesocorticolimbic function can influence the propensity to initiate stimulant use and the risk for stimulant use disorders. Since repeated stimulant use can further alter mesocorticolimbic function, these pathways may serve as a target for both early interventions aimed at preventing the onset of harmful stimulant use and treatments designed to alleviate addiction symptoms. Here we review evidence from studies in both humans and laboratory animals, focusing on the neurotransmitter systems most strongly implicated in StUD, primarily dopamine and, to a lesser extent, glutamate. We identify evidence of (i) complex, non-linear perturbations to mesocorticolimbic function related to stimulant use, and (ii) gaps in knowledge and opportunities for research to improve our understanding of the determinants and consequences of StUD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"18 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025425","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":"Genetic and epigenetic analysis of plasma glial fibrillary acidic protein (GFAP) levels in PTSD","authors":"Mark W. Miller, Xiang Zhao, Erika J. Wolf, William P. Milberg, Catherine B. Fortier, Mark W. Logue","doi":"10.1038/s41380-025-03232-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03232-5","url":null,"abstract":"<p>Glial fibrillary acidic protein (GFAP) is an astrocytic marker that can be assessed in blood using single molecule array technology. Recent studies suggest that individuals with posttraumatic stress disorder (PTSD) have suppressed circulating levels of this CNS biomarker. This study examined the hypothesis that PTSD and plasma GFAP levels share common genetic and epigenetic pathways. Using data from 1096 veterans and civilians, we computed a PTSD polygenic risk score (PRS) derived from a prior PTSD genomewide association study (GWAS) and found that PTSD severity and the PRS were each associated with reduced levels of GFAP. To clarify the basis of the PRS association, we performed a GWAS of GFAP which identified 20 genomewide-significant loci including genes implicated in independent GWASs of PTSD and neurodegenerative disease (e.g., <i>PRKN, NFIA)</i>. Comparison of the PTSD and GFAP GWAS results showed that PTSD-associated genes were significantly enriched in the GFAP results with notable overlap involving <i>NPSR1</i> and the <i>protocadherin alpha</i> (<i>PCDHA</i>) gene cluster. Similarly, we performed an epigenomewide association study (EWAS) of GFAP, which identified 4 genomewide-significant associations (including loci in <i>MCT4</i> and <i>SREBF1</i>) and then compared those results to the findings of a PTSD EWAS. Results again showed significantly greater overlap than would be expected by chance and included loci implicated in prior studies of depression, dementia, and inflammation. This study clarifies the genetic and epigenetic basis of the association between PTSD and plasma GFAP levels and should encourage future research into the role of GFAP in the pathophysiology of PTSD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"44 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025429","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":"Dopaminergic frontostriatal pathways in major depressive disorder and childhood sexual abuse: a multimodal neuroimaging investigation","authors":"Lauren R. Borchers, Rotem Dan, Emily L. Belleau, Roselinde H. Kaiser, Rachel Clegg, Franziska Goer, Pia Pechtel, Miranda Beltzer, Dustin Wooten, Georges El Fakhri, Marc D. Normandin, Diego A. Pizzagalli","doi":"10.1038/s41380-025-03218-3","DOIUrl":"https://doi.org/10.1038/s41380-025-03218-3","url":null,"abstract":"<p>Dysregulated dopaminergic signaling has been implicated in the pathophysiology of major depressive disorder (MDD) and childhood sexual abuse (CSA), but inconsistencies abound. In a multimodal PET-functional MRI study, harnessing the highly selective tracer [¹¹C]altropane, we investigated dopamine transporter availability (DAT) and resting-state functional connectivity (rsFC) within reward-related regions among 112 unmedicated individuals (MDD: <i>n</i> = 37, MDD/CSA: <i>n</i> = 18; CSA no MDD: <i>n</i> = 14; controls: <i>n</i> = 43). Striatal DAT and seed-based rsFC were assessed in the dorsal and ventral striatum and the ventral tegmental area. We found that MDD, CSA, and their co-occurrence were associated with region-specific DAT abnormalities, which were related to the number of lifetime MDD episodes and the duration of childhood maltreatment. CSA was further associated with lower frontostriatal rsFC. The findings provide compelling evidence of DA dysregulation in MDD and CSA, and highlight potential prevention and treatment targets.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"39 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017550","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":"From early-life fluoxetine exposure to lifelong, sex-specific behavioral changes: decoding the dynamics of sensitive periods","authors":"Maria Teresa Gallo, Anaïs Virenque, Alessia Golinelli, Fabio Fumagalli, Eero Castrén, Paola Brivio, Francesca Calabrese","doi":"10.1038/s41380-025-03223-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03223-6","url":null,"abstract":"<p>Early-life experiences shape neural networks, with heightened plasticity during the so-called “sensitive periods” (SP). SP are regulated by the maturation of GABAergic parvalbumin-positive (PV+) interneurons, which become enwrapped by perineuronal nets (PNNs) over time, modulating SP closure. Additionally, the opening and closing of SP are orchestrated by two distinct gene clusters known as “trigger” and “brake”. Interestingly alterations in SP markers have been identified in neuropsychiatric disorders, suggesting they may play a role in the emergence of these pathological conditions. Here, we investigate, in rats, whether the behavioral phenotypes observed in adults exposed to fluoxetine (FLX) during gestation or breastfeeding (until postnatal day 21) are due to alterations in SP dynamics. In line with the pathological-like adult phenotypes observed, the molecular results reveal a clear sex difference with significant changes in the density of PV+, in the proportion of PV+ cells surrounded by PNNs, as well as in the expression of trigger and brake genes across the lifespan, in the prefrontal cortex and dorsal hippocampus. In particular, we observed the strongest effect in the dentate gyrus (DG) of the dorsal hippocampus, with an anticipation in prenatal-FLX males and a delay in postnatal-FLX females of SP opening. We suggest that the molecular targets herein described may represent useful biomarkers to identify people with potentially increased vulnerability and, accordingly, we can hypothesize that strategies (pharmacological or not) aimed at correcting these abnormalities may be useful in preventing the pathological manifestation.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025430","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":"Neural correlates of peripartum depression: a systematic review, meta-analysis and comparison to major depressive disorder","authors":"Mónica Sobral, Raquel Guiomar, Manya Rezaeian, Maria Vasileiadi, Sara Cruz, Francisca Pacheco, Vera Mateus, Roser Palau-Costafreda, Johanna Pozo-Neira, Ana Weidenauer, Helena Moreira, Martin Tik, Ana Ganho-Ávila, Anna-Lisa Schuler","doi":"10.1038/s41380-025-03227-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03227-2","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Peripartum depression (PPD) is a form of major depressive disorder (MDD) that begins during the peripartum period and poses a significant mental health challenge affecting 10 to 29% of women.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>This systematic review and multimodal activation likelihood estimation (ALE) meta-analysis explored the distinct structural, functional, and metabolic features of the PPD brain as compared to female non-peripartum MDD.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>For this purpose, we conducted a comprehensive literature search in PubMed, Embase and PsycINFO databases to identify peer-reviewed original studies investigating the neural correlates associated with PPD or fMDD.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Forty-five studies in PPD and 55 in fMDD were included in the qualitative synthesis. From these, 25 PPD and 32 fMDD studies were included in the meta-analysis. Both shared and distinct neural underpinnings of PPD and fMDD were observed. Specifically, we found alterations in the cognitive control, salience and default mode networks for both PPD and fMDD, although with reversed structural and functional activity patterns in the insula, amygdala, precentral gyrus and precuneus.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>These findings support the consistent pattern of dysregulation associated with emotional regulation, cognition and maternal caregiving in women with PPD, as well as possible differential sensitivity to hormonal influences, highlighting the need for targeted interventions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"69 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017555","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":"Polygenic scores for psychiatric traits mediate the impact of multigenerational history for depression on offspring psychopathology","authors":"Eunji Lee, Milenna T. van Dijk, Bo-Gyeom Kim, Gakyung Kim, Eleanor Murphy, Ardesheer Talati, Yoonjung Yoonie Joo, Myrna M. Weissman, Jiook Cha","doi":"10.1038/s41380-025-03221-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03221-8","url":null,"abstract":"<p>A family history of depression is a well-documented risk factor for offspring psychopathology. However, the genetic mechanisms underlying the intergenerational transmission of depression remain unclear. We used genetic, family history, and diagnostic data from 11,875 9–10 year-old children from the Adolescent Brain Cognitive Development study. We estimated and investigated the children’s polygenic scores (PGSs) for 30 distinct traits and their association with a family history of depression (including grandparents and parents) and the children’s overall psychopathology through logistic regression analyses. We assessed the role of polygenic risk for psychiatric disorders in mediating the transmission of depression from one generation to the next. Among 11,875 multi-ancestry children, 8111 participants had matching phenotypic and genotypic data (3832 female [47.2%]; mean (SD) age, 9.5 (0.5) years), including 6151 [71.4%] of European-ancestry). Greater PGSs for depression (estimate = 0.129, 95% CI = 0.070–0.187) and bipolar disorder (estimate = 0.109, 95% CI = 0.051–0.168) were significantly associated with higher family history of depression (Bonferroni-corrected <i>P</i> &lt; 0.05). Depression PGS was the only PGS that significantly associated with both family risk and offspring’s psychopathology, and robustly mediated the impact of family history of depression on several youth psychopathologies including anxiety disorders, suicidal ideation, and any psychiatric disorder (proportions mediated 1.39–5.87% of the total effect on psychopathology; FDR-corrected <i>P</i> &lt; 0.05). These findings suggest that increased polygenic risk for depression partially mediates the associations between family risk for depression and offspring psychopathology, showing a genetic basis for intergenerational transmission of depression. Future approaches that combine assessments of family risk with polygenic profiles may offer a more accurate method for identifying children at elevated risk.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"34 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017552","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":"Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons","authors":"Komal Saleem, Zichun Xiao, Binglin Zhu, Yong Ren, Zhen Yan, Jian Feng","doi":"10.1038/s41380-025-03225-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03225-4","url":null,"abstract":"<p>Hyperphosphorylation of Tau and the ensuing microtubule destabilization are linked to synaptic dysfunction in Alzheimer’s disease (AD). We find a marked increase of phosphorylated Tau (pTau) in cortical neurons differentiated from induced pluripotent stem cells (iPSCs) of AD patients. It is accompanied by significantly elevated expression of Serum and Glucocorticoid-regulated Kinase-1 (SGK1), which is induced by cellular stress, and Histone Deacetylase 6 (HDAC6), which deacetylates tubulin to destabilize microtubules. Indeed, acetylated tubulin and microtubule stability are significantly lower in AD-derived cortical neurons. SGK1 inhibitors or shRNA decrease Tau phosphorylation and HDAC6 levels while increasing acetylated tubulin in AD neurons. Overexpression of SGK1 in normal neurons does the opposite. These results suggest that elevation of the cellular stress-induced SGK1 increases Tau phosphorylation and HDAC6 expression, which destabilize microtubules to compromise many cellular functions subserving cognition. The coordinated increases in SGK1, pTau, and HDAC6, as well as the corresponding decrease in acetylated tubulin and microtubule stability in AD neurons, offer attractive targets for therapeutic development.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017554","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}