Molecular Psychiatry最新文献

{"title":"Genetic and neural mechanisms shared by schizophrenia and depression","authors":"Yingying Xie, Jilian Fu, Liping Liu, Xijin Wang, Feng Liu, Meng Liang, Hesheng Liu, Wen Qin, Chunshui Yu","doi":"10.1038/s41380-025-02975-5","DOIUrl":"https://doi.org/10.1038/s41380-025-02975-5","url":null,"abstract":"<p>Schizophrenia (SCZ) and depression are two prevalent mental disorders characterized by comorbidity and overlapping symptoms, yet the underlying genetic and neural mechanisms remain largely elusive. Here, we investigated the genetic variants and neuroimaging changes shared by SCZ and depression in Europeans and then extended our investigation to cross-ancestry (Europeans and East Asians) populations. Using conditional and conjunctional analyses, we found 213 genetic variants shared by SCZ and depression in Europeans, of which 82.6% were replicated in the cross-ancestry population. The shared risk variants exhibited a higher degree of deleteriousness than random and were enriched for synapse-related functions, among which fewer than 3% of shared variants showed horizontal pleiotropy between the two disorders. Mendelian randomization analyses indicated reciprocal causal effects between SCZ and depression. Using multiple trait genetic colocalization analyses, we pinpointed 13 volume phenotypes shared by SCZ and depression. Particularly noteworthy were the shared volume reductions in the left insula and planum polare, which were validated through large-scale meta-analyses of previous studies and independent neuroimaging datasets of first-episode drug-naïve patients. These findings suggest that the shared genetic risk variants, synapse dysfunction, and brain structural changes may underlie the comorbidity and symptom overlap between SCZ and depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766628","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":"Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients","authors":"Leslie G. Nucifora, Koko Ishizuka, Nagat El Demerdash, Brian J. Lee, Michael T. Imai, Carlos Ayala-Grosso, Gayane Yenokyan, Nicola G. Cascella, Sandra Lin, David J. Schretlen, Philip D. Harvey, Russell L. Margolis, Christopher A. Ross, Akira Sawa, Frederick C. Nucifora","doi":"10.1038/s41380-025-02956-8","DOIUrl":"https://doi.org/10.1038/s41380-025-02956-8","url":null,"abstract":"<p>Schizophrenia is a heterogeneous disorder, and likely results from multiple pathophysiological mechanisms. Protein aggregation, resulting from disruption of protein homeostasis (proteostasis), has been implicated in many diseases, including cancer, cardiac and pulmonary diseases, muscle diseases, and neurodegenerative disorders, but is a relatively new pathophysiological hypothesis for schizophrenia. Genetic findings implicate proteostasis in schizophrenia, and individual proteins associated with the disorder may undergo aggregation. While there is some evidence of associations between genetic variants and protein aggregation, the extent to which genetic variations influence protein aggregation remains unknown. We have previously reported increased protein insolubility and increased ubiquitination of the insoluble protein fraction, two markers of protein aggregation, in human postmortem brains from a subset of patients with schizophrenia. In the present study, we investigate whether protein aggregation is observed in an independent model system, olfactory neuronal cells derived from living patients with schizophrenia, and examine the relationship between aggregation and patient clinical and cognitive status. We demonstrate that, as in postmortem brain, olfactory neurons from a subset of patients with schizophrenia exhibit protein aggregation, identified by increased protein insolubility and ubiquitination of the insoluble protein fraction, and by ubiquitin positive protein aggregates. Patients with protein aggregation exhibit more severe cognitive deficits than those without aggregation, as revealed by between-group comparisons and correlational analyses. Understanding the mechanisms of the aggregation process, the factors that differentiate individuals who develop aggregates from those who do not, and the relationship between aggregation and cell function, has important implications for the pathophysiology of schizophrenia, and may provide insight into disease heterogeneity and novel therapeutic targets.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"62 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766629","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":"RVG engineered extracellular vesicles-transmitted miR-137 improves autism by modulating glucose metabolism and neuroinflammation","authors":"Qian Qin, Mengyue Li, Linlin Fan, Xin Zeng, Danyang Zheng, Han Wang, Yutong Jiang, Xinrui Ma, Lei Xing, Lijie Wu, Shuang Liang","doi":"10.1038/s41380-025-02988-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02988-0","url":null,"abstract":"<p>Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder. The microglia activation is a hallmark of ASD, which involves increased glycolysis. Elevated glycolysis regardless of oxygen availability, known as “Warburg effect”, is crucial to pathogenesis in neuropsychiatric disorders. Psychiatric risk gene <i>MIR137</i> plays an important role in neurogenesis and neuronal maturation, but the impact on neuroinflammation and glucose metabolism remains obscure. Extracellular vesicles (EVs) can delivery miR-137 crossing the blood-brain barrier. Meanwhile, EVs can help miR-137 avoid being rapidly degraded by endogenous nucleases. Here, after first detecting miR-137 decreased both in the peripheral blood of individuals with ASD and the serum and cerebellum of BTBR mice, we demonstrated that microglia activation, the level of lactate and key enzymes (HK2, PKM2 and LDHA) involved in glycolysis were increased significantly in BTBR mice. Of particular note, EVs engineered by rabies virus glycoprotein (RVG) could promote the miR-137 (RVG-miR137-EVs) targeted to the brain accurately, and alleviated autism-like behaviors. Pro-inflammatory activation of BTBR mice was considerably inhibited by RVG-miR137-EVs via tail vein administration, accompanied by decreased lactate production. Mechanically, these effects were attributed to <i>TLR4</i>, the key target gene, which was regulated by miR-137. The TLR4/NF-κB pathway was inhibited, subsequently reducing HIF-1α and repressing the transcription of HK2, PKM2 and LDHA involved in glycolysis. Pharmacological inhibition of glycolysis and TLR4 attenuated microglial activation and lactate production, ultimately improved autism-like behaviors of BTBR mice. In conclusion, our results indicated that miR-137 could alleviate autism-like behaviors by HIF-1α-mediated adaptive metabolic changes in glycolysis and neuroinflammation.</p><figure></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"58 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766632","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":"Mettl3 regulates the pathogenesis of Alzheimer’s disease via fine-tuning Lingo2","authors":"Xingsen Zhao, Chengyi Ma, Qihang Sun, Xiaoli Huang, Wenzheng Qu, Yusheng Chen, Ziqin Liu, Aimin Bao, Binggui Sun, Ying Yang, Xuekun Li","doi":"10.1038/s41380-025-02984-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02984-4","url":null,"abstract":"<p>Alzheimer’s disease (AD) is the most common neurodegenerative disease, and diverse factors contribute to its pathogenesis. Previous studies have suggested the dysregulation of m⁶A modification involves in AD, but the underlying mechanism and targets remain largely unknown. In the present study, we have shown that the levels of Mettl3 and m⁶A modification are increased in specific brain regions of 5xFAD mice and post-mortem AD patients, respectively. Heterozygous deletion of neuronal <i>Mettl3</i> (AD::<i>Mettl3</i>^+/−) reduced Aβ plaques and inflammation, and improved learning and memory of AD mice, and vice versa for <i>Mettl3</i> knock in (AD::<i>Mettl3</i>-KI). Mechanistically, we observed that the level of m⁶A modification of <i>Lingo2</i> increased in 5xFAD mice and AD patients, which promoted the binding of Ythdf2 and enhanced the degradation of <i>Lingo2</i> mRNA. The decreased level of Lingo2 promoted the interaction between APP and β-site amyloid precursor protein cleaving enzyme (Bace1), and subsequently enhanced Aβ production in AD mice, which can be inhibited by <i>Mettl3</i> depletion. Both ectopic <i>Lingo2</i> and the administration of Mettl3 inhibitor STM2457 significantly alleviated the neuropathology and behavioral deficits of AD mice. In summary, our study has revealed the important function of Mettl3 and m⁶A in the pathogenesis of AD and provided novel insight for the underlying mechanisms. Our study also suggests that m⁶A and <i>Lingo2</i> could be potential therapeutic targets for AD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"23 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758093","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":"Bidirectional causal associations between plasma metabolites and bipolar disorder","authors":"Qian Zhao, Ancha Baranova, Dongming Liu, Hongbao Cao, Fuquan Zhang","doi":"10.1038/s41380-025-02977-3","DOIUrl":"https://doi.org/10.1038/s41380-025-02977-3","url":null,"abstract":"<p>Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performed a bidirectional metabolome-wide Mendelian randomization (MR) analysis to evaluate the potential causal relationships between 871 plasma metabolites and BD. We used DrugBank and ChEMBL to evaluate whether related metabolites are potential therapeutic targets. Finally, Bayesian colocalization analysis was performed to identify shared genomic loci BD and identified metabolites. Our MR results showed that six metabolites were significantly associated with a reduced risk of BD, including arachidonate (20:4n6) (OR: 0.90, 95% CI: 0.84–0.95) and sphingomyelin (d18:2/24:1, d18:1/24:2) (OR: 0.92, 95% CI: 0.87–0.96), while five metabolites were significantly associated with an increased risk of BD, including 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (OR: 1.09, 95% CI: 1.05–1.13). However, our reverse MR analysis showed that BD was not associated with the levels of any metabolite. Additionally, the leave-one-out analysis revealed SNPs within chromosome 11 loci harboring <i>MYRF</i>, <i>FADS1</i>, and <i>FADS2</i> as ones with the potential to influence partial causal effects. Druggability evaluation showed that 10 of the BD-related metabolites, such as sphingomyelin and cytidine, have been targeted by pharmacologic intervention. Colocalization analysis highlighted one colocalized region (chromosome 11q12) shared by 11 metabolites and BD and pointed to some genes as possible players, including <i>FADS1</i>, <i>FADS2</i>, <i>FADS3</i>, and <i>SYT7</i>. Our study supported a causal role of plasma metabolites in the susceptibility to BD, and the identified metabolites may provide a new avenue for the prevention and treatment of BD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"64 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758092","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":"Sulforaphane protects developing neural networks from VPA-induced synaptic alterations","authors":"Riley N. Bessetti, Michelle Cobb, Rosario M. Lilley, Noah Z. Johnson, Daisy A. Perez, Virginia M. Koonce, Krista McCoy, Karen A. Litwa","doi":"10.1038/s41380-025-02967-5","DOIUrl":"https://doi.org/10.1038/s41380-025-02967-5","url":null,"abstract":"<p>Prenatal brain development is particularly sensitive to chemicals that can disrupt synapse formation and cause neurodevelopmental disorders. In most cases, such chemicals increase cellular oxidative stress. For example, prenatal exposure to the anti-epileptic drug valproic acid (VPA), induces oxidative stress and synaptic alterations, promoting autism spectrum disorders (ASD) in humans and autism-like behaviors in rodents. Using VPA to model chemically induced ASD, we tested whether activation of cellular mechanisms that increase antioxidant gene expression would be sufficient to prevent VPA-induced synaptic alterations. As a master regulator of cellular defense pathways, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) promotes expression of detoxification enzymes and antioxidant gene products. To increase NRF2 activity, we used the phytochemical and potent NRF2 activator, sulforaphane (SFN). In our models of human neurodevelopment, SFN activated NRF2, increasing expression of antioxidant genes and preventing oxidative stress. SFN also enhanced expression of genes associated with synapse formation. Consistent with these gene expression profiles, SFN protected developing neural networks from VPA-induced reductions in synapse formation. Furthermore, in mouse cortical neurons, SFN rescued VPA-induced reductions in neural activity. These results demonstrate the ability of SFN to protect developing neural networks during the vulnerable period of synapse formation, while also identifying molecular signatures of SFN-mediated neuroprotection that could be relevant for combatting other environmental toxicants.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"27 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766630","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":"Astrocyte morphological remodeling regulates consciousness state transitions induced by inhaled general anesthesia","authors":"Bin Zhou, Qingran Li, Mengchan Su, Ping Liao, Yuncheng Luo, Rong Luo, Yunqing Yu, Meiyan Luo, Fan Lei, Xin Li, Jiao Jiao, Limei Yi, Jing Wang, Linghui Yang, Daqing Liao, Cheng Zhou, Xia Zhang, Hong Xiao, Yunxia Zuo, Jin Liu, Tao Zhu, Ruotian Jiang","doi":"10.1038/s41380-025-02978-2","DOIUrl":"https://doi.org/10.1038/s41380-025-02978-2","url":null,"abstract":"<p>General anesthetics (GAs) are conventionally thought to induce loss of consciousness (LOC) by acting on pre- and post-synaptic targets. However, the mechanism underlying the involvement of astrocytes in LOC remains unclear. Here we report that inhaled GAs cause reversible impairments in the fine processes of astrocytes within the somatosensory cortex, mediated by regulating the phosphorylation level of Ezrin, a protein critical for the fine morphology of astrocytes. Genetically deleting Ezrin or disrupting its phosphorylation was sufficient to decrease astrocyte-synapse interaction and enhance sensitivity to sevoflurane (Sevo) in vivo. Moreover, we show that disrupting astrocytic Ezrin phosphorylation boosted the inhibitory effect of Sevo on pyramidal neurons by enhancing tonic GABA and lowering excitability under anesthesia. Our work reveals previously unappreciated phosphorylation-dependent morphological dynamics, which enable astrocytes to regulate neuronal activity during the transition between two brain consciousness states.</p><figure></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"22 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744879","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":"Differential impact of cerebral small vessel disease on thalamic regulation of anxiety: insights from 7T MRI","authors":"Bei Wang, Cen Guo, Ying-Hua Chu, Yajing Huo, Boyu Zhang, Guanshu Liu, Yan Han, He Wang","doi":"10.1038/s41380-025-02994-2","DOIUrl":"https://doi.org/10.1038/s41380-025-02994-2","url":null,"abstract":"<p>Little is known about how thalamic vascular patterns interact with small vessel diseases (SVDs) to influence affective symptoms. Here we collected 7-Telsa magnetic resonance imaging (MRI) data from 84 individuals with SVD and analyzed the influences of thalamic vascular pattern on affective symptoms, aiming to elucidate the underlying mechanisms driven by brain structure and function in the context of SVD. Subjects with a combined arterial supply by tuberothalamic and paramedian arteries to the right thalamus exhibited a lower Hamilton Anxiety scale (HAMA) score. When grouped by SVD burden, the same correlation remained in subjects with low SVD burden, whereas no difference was observed in the high SVD burden group. Interestingly, interaction effects of SVD and thalamic vascular pattern were also found affecting thalamic volume and resting-state brain activity in ventromedial prefrontal cortex (vmPFC). With moderated mediation analysis, right thalamic vascular pattern was indicated to affect anxiety through both direct (vascular pattern → HAMA score) and indirect (vascular pattern → thalamic volume → HAMA score) pathways. But high SVD burden interrupted the effects of right thalamic vascular pattern on HAMA score and thalamic volume. The finding that subjects with a combined arterial supply to the right thalamus exhibited a lower level of anxiety may suggest a novel vascular resilience for regulating anxiety. However, this vascular compensation mechanism was found to be impaired by elevated SVD burden and the disrupted inhibitory vmPFC activity caused by impaired thalamus. The findings of the present study provide a new underlying mechanism for affective disorders with SVD involved.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758094","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":"Association between the childhood rearing environment and general and specific psychopathology factors in middle adulthood: a Swedish National High-Risk Home-Reared versus Adopted-Away Sibling Comparison Study","authors":"Mengping Zhou, Henrik Larsson, Brian M. D’Onofrio, Mikael Landén, Paul Lichtenstein, Erik Pettersson","doi":"10.1038/s41380-025-02979-1","DOIUrl":"https://doi.org/10.1038/s41380-025-02979-1","url":null,"abstract":"<p>Quasi-experimental and randomized controlled studies suggest that an enriched childhood rearing environment for at-risk individuals can reduce the risk for several psychiatric conditions. However, it remains uncertain if the reduced risk might be attributable to a general psychopathology factor common to all psychiatric conditions, versus specific psychopathology factors unique to only subsets of psychiatric conditions. In an at-risk sample, we estimated the association between an enriched childhood rearing environment and a latent bifactor model that captured both general and several specific psychopathology factors. The sample consisted of 881 full sibships where (a) the biological parents had (at least) one psychiatric diagnosis, suicide, or crime at any time in their lives, and (b) where (at least) one sibling was adopted away and raised by non-biological parents and (at least) one sibling raised by the biological parents. The exposure was whether a sibling was raised by biological versus adoptive parents. The outcome was a latent bifactor model based on nine conditions, including 7 in- or outpatient psychiatric diagnoses, suicide, and crimes. We recorded these outcomes from the birth of the siblings until the end of 2013, when the siblings were 34–64 years old. We used the marginal between-within model to estimate whether the adopted-away sibling(s) had lower scores on the latent factors. The latent bifactor model based on the nine conditions consisted of one general and three specific (externalizing, internalizing, and psychotic) psychopathology factors. The adopted-away siblings scored 0.27 (95% CI: −0.36, −0.18) standard deviations lower on the latent general psychopathology factor and 0.26 (95% CI: −0.38, −0.14) standard deviations lower on the latent specific externalizing factor, compared to their biological siblings who were raised by the biological parents. This result indicates that although genetics appears important for psychiatric comorbidity, the rearing environment also appears to play a systematic role in influencing the liability toward all mental health conditions among at-risk individuals. Improving the childhood rearing environment in high-risk families could potentially mitigate children’s liability toward all psychiatric conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"15 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744881","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":"Higher plasma soluble TREM2 correlates with reduced cerebral tau accumulation in Alzheimer’s disease","authors":"Guoyu Lan, Anqi Li, Fernando Gonzalez-Ortiz, Jieqin Lv, Wenqing Ran, Yue Cai, Pan Sun, Lin Liu, Jie Yang, Laihong Zhang, Zhengbo He, Lili Fang, Xin Zhou, Yalin Zhu, Zhen Liu, Xiang Fan, Xuhui Chen, Linsen Xu, Qingyong Wang, Xinlu Wang, Kun Sun, Guanxun Cheng, Ying Han, Kaj Blennow, Lu Wang, Pengcheng Ran, Tengfei Guo","doi":"10.1038/s41380-025-02976-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02976-4","url":null,"abstract":"<p>Loss-of-function mutation of triggering receptor expressed on myeloid cell 2 (TREM2) is associated with increased risks for Alzheimer’s disease (AD). Recent animal studies reveal that the activation of peripheral TREM2 signaling may affect cerebral β-amyloid (Aβ) and tau aggregates. However, the underlying relationship between peripheral TREM2 and brain AD pathology has not yet been well-elucidated in the aging population. In this study, we collected 318 Chinese older adults with Aβ PET and plasma biomarker measures, including soluble TREM2 (sTREM2) and glial fibrillary acidic protein (GFAP), a proxy for astrocyte reactivity. Additionally, 129 participants underwent tau PET scans. We explored the association between plasma sTREM2, GFAP, and primary AD pathology. Plasma sTREM2 was negatively associated with reduced temporal tau PET burden in participants with abnormal Aβ and tau pathology. Higher plasma sTREM2 was related to the weaker association of Aβ pathology and plasma phosphorylated tau with tau PET increases. In contrast, elevated plasma GFAP was related to greater Aβ and tau PET burden along with stronger Aβ-related tau accumulation. Finally, higher plasma sTREM2 was linked to attenuated strength of the association between plasma GFAP and tau PET increases at both pre-defined regions of interest and voxel levels. Altogether, our findings suggest distinct relationships between plasma sTREM2 and GFAP with cerebral tau pathology, providing novel insights into the roles of peripheral TREM2 signaling and astrocytic reactivity in AD neuropathological development. This study has important implications, such as targeting the peripheral TREM2 signature, which may be a potential strategy for future AD therapies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"12 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744880","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}