Molecular Brain最新文献

Klotho overexpression protects human cortical neurons from β-amyloid induced neuronal toxicity.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-28 DOI: 10.1186/s13041-025-01199-6

Mohammed R Shaker, Salam Salloum-Asfar, Rowaida Z Taha, Ibrahim Javed, Ernst J Wolvetang

{"title":"Klotho overexpression protects human cortical neurons from β-amyloid induced neuronal toxicity.","authors":"Mohammed R Shaker, Salam Salloum-Asfar, Rowaida Z Taha, Ibrahim Javed, Ernst J Wolvetang","doi":"10.1186/s13041-025-01199-6","DOIUrl":"https://doi.org/10.1186/s13041-025-01199-6","url":null,"abstract":"Klotho, a well-known aging suppressor protein, has been implicated in neuroprotection and the regulation of neuronal senescence. While previous studies have demonstrated its anti-aging properties in human brain organoids, its potential to mitigate neurodegenerative processes triggered by β-amyloid remains underexplored. In this study, we utilised human induced pluripotent stem cells (iPSCs) engineered with a doxycycline-inducible system to overexpress KLOTHO and generated 2D cortical neuron cultures from these cells. These neurons were next exposed to pre-aggregated β-amyloid 1-42 oligomers to model the neurotoxicity associated with Alzheimer's disease. Our data reveal that upregulation of KLOTHO significantly reduced β-amyloid-induced neuronal degeneration and apoptosis, as evidenced by decreased cleaved caspase-3 expression and preservation of axonal integrity. Additionally, KLOTHO overexpression prevented the loss of dendritic branching and mitigated reductions in axonal diameter, hallmark features of neurodegenerative pathology. These results highlight Klotho's protective role against β-amyloid-induced neurotoxicity in human cortical neurons and suggest that its age-related decline may contribute to neurodegenerative diseases such as Alzheimer's disease. Our findings underscore the therapeutic potential of Klotho-based interventions in mitigating age-associated neurodegenerative processes.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"27"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional characterization of a novel de novo CACNA1C pathogenic variant in a patient with neurodevelopmental disorder.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-25 DOI: 10.1186/s13041-025-01195-w

Robin N Stringer, Xuechen Tang, Bohumila Jurkovicova-Tarabova, Mary Murphy, Klaus R Liedl, Norbert Weiss

{"title":"Functional characterization of a novel de novo CACNA1C pathogenic variant in a patient with neurodevelopmental disorder.","authors":"Robin N Stringer, Xuechen Tang, Bohumila Jurkovicova-Tarabova, Mary Murphy, Klaus R Liedl, Norbert Weiss","doi":"10.1186/s13041-025-01195-w","DOIUrl":"10.1186/s13041-025-01195-w","url":null,"abstract":"Mutations in CACNA1C, the gene encoding Cav1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Cav1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C-related disorders.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"26"},"PeriodicalIF":3.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neural stem cell-specific deletion of Atg7 alleviates hippocampal dysfunction and neuronal alterations induced by chronic restraint stress.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-21 DOI: 10.1186/s13041-025-01189-8

Hyeonjeong Jeong, Seongwon Choe, Seonghee Jung, Seong-Woon Yu

{"title":"Neural stem cell-specific deletion of Atg7 alleviates hippocampal dysfunction and neuronal alterations induced by chronic restraint stress.","authors":"Hyeonjeong Jeong, Seongwon Choe, Seonghee Jung, Seong-Woon Yu","doi":"10.1186/s13041-025-01189-8","DOIUrl":"10.1186/s13041-025-01189-8","url":null,"abstract":"Adult hippocampal neurogenesis is inhibited by chronic psychological stress and impaired neurogenesis underlies stress-related psychological disorders. We previously reported that chronic restraint stress (CRS) evokes autophagic death of adult hippocampal neural stem cells (NSCs) while NSC-specific deletion of Atg7 prevents death of NSCs. Examination of cognitive ability and mood regulation next day of the termination of stress showed normal hippocampal function in mice deficient of Atg7. However, it was not investigated whether the preservation of NSC pool alleviates hippocampal neuronal alterations. Here, we show that CRS increased c-Fos-positive, activated neurons in the granule cell layer and decreased spine density of CA3 neurons in the hippocampus, and these hippocampal neuronal deficits were prevented by NSC-specific deletion of Atg7. Of note, our observation was conducted right after the termination of CRS. Therefore, our results suggest that the detrimental effects of stress on hippocampal neurons can be buffered by NSCs independent of neurogenesis and NSCs are essential to the hippocampal function both through the neurogenesis-dependent developmental process and by direct regulation of neural activation.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"25"},"PeriodicalIF":3.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: The properties of TREM1 and its emerging role in pain-related diseases.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-20 DOI: 10.1186/s13041-025-01193-y

Zhenzhen Fan, Longde Wang, Songtang Sun, Zhaoming Ge

引用次数: 0

The terpenes alpha-bisabolol and camphene modulate pruritus via an action on Cav3.2 T-type calcium channels.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-18 DOI: 10.1186/s13041-025-01196-9

Flavia T T Antunes, Vinicius M Gadotti, Gerald W Zamponi

{"title":"The terpenes alpha-bisabolol and camphene modulate pruritus via an action on Cav3.2 T-type calcium channels.","authors":"Flavia T T Antunes, Vinicius M Gadotti, Gerald W Zamponi","doi":"10.1186/s13041-025-01196-9","DOIUrl":"10.1186/s13041-025-01196-9","url":null,"abstract":"Alpha-bisabolol and camphene have demonstrated analgesic effects in inflammatory pain models by blocking Cav3.2 calcium channels. As the pain pathway overlaps with mechanisms for itch, and because Cav3.2 channels have been associated with itch in our previous work, we aimed to investigate the potential anti-itch effects of these two terpenes. Although both terpenes failed to show anti-pruritogenic properties when dissolved in aqueous PBS, when diluted in Hydroxypropyl-beta-cyclodextrin their bioactivity significantly increased. Both compounds significantly reduced scratching in the histaminergic itch model, whether administered subcutaneously or intraperitoneally. Camphene reduced itching in the non-histaminergic model regardless of the route of administration, whereas alpha-bisabolol did not alleviate chloroquine-induced itching. When tested in Cav3.2-/- mice, neither camphene nor alpha-bisabolol significantly reduced histamine-induced scratching behavior. This suggests that the anti-pruritic actions of these terpenes may involve Cav3.2 block to mitigate itch.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"22"},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The psychedelic psilocybin and light exposure have similar and synergistic effects on gene expression patterns in the visual cortex.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-18 DOI: 10.1186/s13041-025-01191-0

Ram Harari, Dmitriy Getselter, Evan Elliott

{"title":"The psychedelic psilocybin and light exposure have similar and synergistic effects on gene expression patterns in the visual cortex.","authors":"Ram Harari, Dmitriy Getselter, Evan Elliott","doi":"10.1186/s13041-025-01191-0","DOIUrl":"10.1186/s13041-025-01191-0","url":null,"abstract":"Psilocybin, a psychedelic compound found in specific hallucinogenic mushrooms, is known to induce changes in visual perception and experience in humans. However, there is little knowledge of the molecular mechanisms through which psilocybin affects vision-associated regions in the brain, such as the visual cortex. The current study determined both psilocybin-induced and experience-dependent changes (exposure to light) in visual cortex gene expression in mice. Of great interest, psilocybin induced robust gene expression changes in the visual cortex that closely mirror light-induced gene expression changes, even when the mice are kept in the dark. These gene expression changes correspond to specific molecular pathways, including synaptic functioning, and represent genes expressed in specific subtypes of neurons. In addition, exposure to both psilocybin and light induced synergetic changes in genes involved in epigenetic programming. Overall, the study determined that psilocybin induces robust changes in gene expression in the visual cortex that may have functional consequences in visual perception both in the absence and in synergy with visual experience.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"23"},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Moderate ethanol exposure disrupts energy homesotasis between central and peripheral system in APP/PS1 mice.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-17 DOI: 10.1186/s13041-025-01192-z

Shinwoo Kang, Jeyeon Lee, Paul H Min, Doo-Sup Choi

引用次数: 0

Analysis of neurexin-neuroligin complexes supports an isoform-specific role for beta-neurexin-1 dysfunction in a mouse model of autism.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-14 DOI: 10.1186/s13041-025-01183-0

Francisco Arias-Aragón, Estefanía Robles-Lanuza, Ángela Sánchez-Gómez, Amalia Martinez-Mir, Francisco G Scholl

{"title":"Analysis of neurexin-neuroligin complexes supports an isoform-specific role for beta-neurexin-1 dysfunction in a mouse model of autism.","authors":"Francisco Arias-Aragón, Estefanía Robles-Lanuza, Ángela Sánchez-Gómez, Amalia Martinez-Mir, Francisco G Scholl","doi":"10.1186/s13041-025-01183-0","DOIUrl":"10.1186/s13041-025-01183-0","url":null,"abstract":"Neurexins are presynaptic plasma membrane proteins that regulate key aspects of synapse physiology through the formation of transcellular complexes with postsynaptic ligands, including neuroligins (Nlgns). Each neurexin gene (NRXN1-3) generates two main alternative-spliced transcripts that generate alpha and beta-Nrxn isoforms differing in their extracellular domains. Mutations in NRXN1 are associated with autism and other neurodevelopmental disorders. However, whether dysfunction of NRXN1 occurs through common or isoform-specific postsynaptic partners for alpha- and beta-Nrxn1 is not completely known. The association of Nrxn1 proteins with postsynaptic partners has been mostly analysed in experiments that test binding, but Nrxn proteins must interact with Nlgns in opposing cells, which requires transcellular oligomerization. Here, we studied the interactions of Nrxn1/Nlgn pairs across the synapse and identified the type of association affected in a mouse model of autism. We found that beta-Nrxn1 can be recruited at synaptic contacts by glutamatergic Nlgn1 and GABAergic Nlgn2, whereas alpha-Nrxn1 is a presynaptic partner of Nlgn2. Insertion of alternative spliced segment 4 (AS4) negatively modulates the presynaptic recruitment of Nrxn1 by Nlgns. These data obtained in transcellular assays help clarify previous knowledge based on the ability of Nrxn1 to bind to Nlgns. Interestingly, we found that a mutant beta-Nrxn1 shows ligand restriction for glutamatergic Nlgn1 in the brain of a mouse model of autism. These findings suggest that autism-associated mutations affecting beta-Nrxn1 can act through specific synaptic partners that may be different from those of its alpha-Nrxn1 counterparts.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"20"},"PeriodicalIF":3.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Virally mediated expression of a biologically active peptide to restrain the nuclear functions of ERK1/2 attenuates learning extinction but not acquisition. 通过病毒介导表达具有生物活性的多肽来抑制ERK1/2的核功能，可减轻学习的消退，但不会影响习得。

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-14 DOI: 10.1186/s13041-025-01190-1

Bar Izkovich, Adonis Yiannakas, Sapir Ne'eman, Sailendrakumar Kolatt Chandran, Kobi Rosenblum, Efrat Edry

{"title":"Virally mediated expression of a biologically active peptide to restrain the nuclear functions of ERK1/2 attenuates learning extinction but not acquisition.","authors":"Bar Izkovich, Adonis Yiannakas, Sapir Ne'eman, Sailendrakumar Kolatt Chandran, Kobi Rosenblum, Efrat Edry","doi":"10.1186/s13041-025-01190-1","DOIUrl":"10.1186/s13041-025-01190-1","url":null,"abstract":"Peptide drug technologies offer powerful approaches to develop potent and selective lead molecules for therapeutic and research applications. However, new and optimized delivery approaches are necessary to overcome current pitfalls including fast degradation in cells and tissue. Extracellular signal-regulated kinases 1/2 (ERK1/2) exemplifies proteins that play crucial and varied roles within distinct cellular compartments. Here, we established an innovative method, based on viral vectors, which utilizes the endogenous biogenesis of neurotrophins to deliver and express a biologically active peptide to attenuate specifically ERK1/2 nuclear functions in specific brain area of the adult forebrain. In contrast to our hypothesis, nuclear functions of ERK1/2 in the forebrain are fundamental for the extinction of associative-aversive memories, but not for acquisition, nor for retrieval of these memories. Our research demonstrates the feasibility and applicability of viral vectors to deliver a peptide of interest to manipulate specific molecular processes and/or protein interactions in specific tissue.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"19"},"PeriodicalIF":3.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distinct neural responses of ventromedial prefrontal cortex-projecting nucleus reuniens neurons during aversive memory extinction.

IF 3.3 3区医学

Molecular Brain Pub Date : 2025-03-05 DOI: 10.1186/s13041-025-01185-y

Yuki Mochizuki, Asuka Joji-Nishino, Kazuo Emoto, Akira Uematsu

{"title":"Distinct neural responses of ventromedial prefrontal cortex-projecting nucleus reuniens neurons during aversive memory extinction.","authors":"Yuki Mochizuki, Asuka Joji-Nishino, Kazuo Emoto, Akira Uematsu","doi":"10.1186/s13041-025-01185-y","DOIUrl":"10.1186/s13041-025-01185-y","url":null,"abstract":"Animals adaptively regulate aversive memories in safe environments through extinction, a process central to exposure therapy for anxiety disorders. The limbic thalamus controls cognitive function in concert with interconnected cortical and limbic structures. Though medial prefrontal (mPFC) afferents to the limbic thalamus regulate aversive memory, the functional role of limbic thalamus efferents to mPFC is unclear. Here, we investigated the roles of thalamic nuclei, the reuniens (RE) and mediodorsal (MD) thalamus, projecting to the medial prefrontal cortex (mPFC) in aversive memory conditioning and extinction in male mice. Using retrograde tracing, we demonstrated that ventromedial PFC (vmPFC)- and dorsomedial PFC (dmPFC)-projecting neurons are topologically segregated within the RE and MD. Fiber photometry revealed that both RE→vmPFC and MD→vmPFC neurons respond to aversive stimuli. Notably, RE→vmPFC neurons develop shock-associated cue (CS+) response during aversive conditioning. During extinction, RE→vmPFC neurons exhibited a biphasic response to CS+, while MD→vmPFC neurons showed no cue-evoked activity. Neither optogenetic activation nor inactivation of these populations altered freezing behavior during extinction compared to controls. Collectively, these findings indicate that RE→vmPFC neurons encode aversive cue information during extinction but are dispensable for behavioral modulation. This study highlights the distinct contributions of limbic thalamus-PFC circuits to aversive memory processing.","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"18"},"PeriodicalIF":3.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0