Journal of Neurochemistry最新文献

{"title":"Profiling Plasma Biomarkers, Particularly pTau217 and pTau217/Aβ42, and Their Relation to Cognition in Memory Clinic Patients","authors":"Marco Bucci,&nbsp;Ove Almkvist,&nbsp;Marina Bluma,&nbsp;Nicholas J. Ashton,&nbsp;Irina Savitcheva,&nbsp;Konstantinos Chiotis,&nbsp;Guglielmo Di Molfetta,&nbsp;Kaj Blennow,&nbsp;Henrik Zetterberg,&nbsp;Agneta Nordberg","doi":"10.1111/jnc.70182","DOIUrl":"https://doi.org/10.1111/jnc.70182","url":null,"abstract":"<p>Alzheimer's disease (AD) is characterized by brain protein depositions, impaired synaptic transmission, and progressive cognitive decline. This clinical study, conducted at the tertiary memory clinic of Karolinska University Hospital in Stockholm, evaluates plasma pTau217 (in comparison to other plasma biomarkers) as a non-invasive marker for predicting brain amyloid load and cognitive impairment. Uniquely, it integrates plasma biomarkers with cognitive profiling and amyloid PET to assess diagnostic utility across disease stages in a real-world memory clinic setting. A total of 122 patients underwent extensive clinical examinations, including CSF analysis (used here for clinical diagnosis only), CT/MRI, neuropsychological (NP) testing (<i>n</i> = 80) and blood biomarker measurements. Prior to PET imaging, 74 patients were diagnosed with MCI among other diagnoses (AD, other dementia, no dementia). Following PET, patients were reclassified into diagnostic groups: MCI Aβ− (<i>n</i> = 29), MCI Aβ+ (<i>n</i> = 19), AD (<i>n</i> = 51), other dementias (<i>n</i> = 11). ROC analysis evaluated the ability of plasma biomarkers to predict Aβ-PET positivity. NP test <i>z</i>-scores were reduced into principal components (PCs) using PCA. Plasma pTau217 and pTau217/Aβ42 ratio were elevated in Aβ+ patients compared to MCI Aβ-patients. The ratio distinguished MCI Aβ+ from AD and, together with pTau217, showed the highest predictive value for Aβ positivity in the MCI group among the biomarkers analyzed (AUC 92.8% and 91.4%). Plasma pTau217/Aβ42 ratio was associated with principal component PC2 (“memory encoding and recall”) in MCI Aβ+ (<i>ρ</i> =0.64, p=0.01) and negatively correlated with RAVL retrieval (PC2) in the same group (<i>ρ</i> =−0.57 and −0.6, p=0.028 and 0.017, respectively). Additionally, pTau217 correlated with the “Information” <i>z</i>-score (PC4) in both AD (<i>ρ</i> = −0.50, <i>p</i> = 0.005) and MCI Aβ+ (<i>ρ</i> = 0.53, <i>p</i> = 0.042). Plasma pTau217/Aβ42 might be a valuable predictor of brain amyloid pathology and a potential marker of domain-specific cognitive impairment in AD.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811153","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}

{"title":"Doxorubicin Induces a Senescent Phenotype in Murine and Human Astrocytes","authors":"Mariana Marques,&nbsp;Lívia de Sá Hayashide,&nbsp;Pedro Amorim,&nbsp;Beatriz Martins Fernandes,&nbsp;Ana Paula Bergamo Araujo,&nbsp;Daniel Fernandes Messor,&nbsp;Vitor Emanuel Leocadio,&nbsp;Bruna Pessoa,&nbsp;João Bastos Lima Pacca Corrêa,&nbsp;Cristopher Villablanca,&nbsp;René L. Vidal,&nbsp;Christian González-Billault,&nbsp;Isadora Matias,&nbsp;Flávia Carvalho Alcantara Gomes,&nbsp;Luan Pereira Diniz","doi":"10.1111/jnc.70177","DOIUrl":"https://doi.org/10.1111/jnc.70177","url":null,"abstract":"<p>Aging is a complex biological process that significantly impacts the central nervous system (CNS). Astrocytes, critical support cells in the brain, undergo senescence with age, contributing to neurodegenerative diseases. While previous studies have utilized murine models to investigate astrocyte senescence, human astrocytes offer a more physiologically relevant system to study age-related neurodegenerative changes. This study presents a novel protocol for inducing senescence in both human primary and murine astrocytes using a combination of cellular stressors, such as lactacystin, H₂O₂, rotenone, and doxorubicin. Our results demonstrate that doxorubicin treatment effectively induces a robust senescent phenotype in both human and murine astrocytes, characterized by increased expression of senescence markers such as p21 and β-galactosidase, along with activation of the DNA damage response (γ-H2AX and 53BP1). Doxorubicin treatment increased nuclear size and induced cell cycle arrest in astrocytes, as revealed by reduced BrdU incorporation and decreased cell density, without inducing cytotoxic effects. This phenotype is accompanied by a pronounced pro-inflammatory profile, with elevated expression of cytokines including MMP3, IL-6, and IL-1β, indicative of a strong senescence-associated secretory phenotype (SASP). These findings provide a novel in vitro model for murine and human astrocyte senescence induced by doxorubicin, highlighting its relevance for studying mechanisms underlying age-related neuroinflammation and neurodegeneration. By establishing a robust model of human astrocyte senescence, this study provides a valuable tool for exploring the molecular and cellular mechanisms driving age-related neurodegenerative processes, serving as an alternative approach to traditional murine models.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773795","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}

{"title":"The Tacrine-Induced Endoplasmic Reticulum Stress in AChE-Expressed Cells Leads to Improper Assembly and Transport of the Oligomeric Enzyme: Reversal by Trehalose","authors":"Xiaoyang Wang,&nbsp;Yingjie Xia,&nbsp;Maggie Suisui Guo,&nbsp;Jiahui Wu,&nbsp;Ajiaikebaier Dilidaer,&nbsp;Jin Gao,&nbsp;Tina Tingxia Dong,&nbsp;Yue Zhu,&nbsp;Karl Wah Keung Tsim","doi":"10.1111/jnc.70178","DOIUrl":"https://doi.org/10.1111/jnc.70178","url":null,"abstract":"<p>Alzheimer's disease (AD) is the most common dementia with progressive loss of cognitive functions. Acetylcholinesterase (AChE) inhibitors have been approved as conventional pharmacotherapies for AD. Tacrine was the first AChE inhibitor introduced into clinics for AD; however, it was withdrawn from use in 2013 because of safety concerns. In cultured neurons, as well as in mice, tacrine was found to induce endoplasmic reticulum (ER) stress and finally lead to cell apoptosis: the event was triggered by binding the inhibitor to the intracellular enzyme serving as a pharmacological chaperone. Trehalose, a known ER stress reducer, was shown here to ameliorate the ER stress induced by tacrine in AChE-overexpressed NG108-15 cells, with the increased level of C/EBP homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α). In tetrameric G4 AChE overexpressed cells, the tacrine-exposed cultures revealed considerable G1/G2 forms of AChE accumulated in the ER fraction, whereas the treatment of trehalose decreased the accumulation of G1/G2 AChE. Meanwhile, trehalose reduced the ER stress induced by other AChE inhibitors, for example, lycobetaine, bis(3)-cognitin, daurisoline, and dauricine, in the cultured neuronal cells. Besides, this tacrine-induced ER stress was identified in all AChE isoforms, as well as in butyrylcholinesterase (BChE) expressing cells. Thus, we proposed that the AChE inhibitors, particularly tacrine, could act as ‘chemical/pharmacological chaperones’ during AChE biosynthesis in the ER, disrupting the proper folding of AChE in neurons as a result of ER stress. Trehalose possesses the ability to relieve ER stress by promoting the proper assembly of AChE. The results provide guidance for the drug design and discovery of AChE inhibitors for AD treatment.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773798","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}

{"title":"Botulinum Neurotoxins: History, Mechanism, and Applications. A Narrative Review","authors":"Arik Monash,&nbsp;Joseph Tam,&nbsp;Osnat Rosen,&nbsp;Hermona Soreq","doi":"10.1111/jnc.70187","DOIUrl":"https://doi.org/10.1111/jnc.70187","url":null,"abstract":"<p>Botulinum neurotoxins (BoNTs), produced by <i>Clostridium botulinum</i>, exert their potent neuroparalytic effects by specifically targeting presynaptic cholinergic nerve terminals. BoNTs consist of a heavy chain that mediates high-affinity neuronal binding and endocytosis, and a light chain that, once translocated into the cytosol, acts as a zinc-dependent metalloprotease. The light chain cleaves SNARE proteins essential for synaptic vesicle fusion, thereby inhibiting acetylcholine release and leading to flaccid paralysis. This intoxication spans foodborne, wound, and infant botulism, all characterized by commonly observed heat-resistant endospores that enable bacterial survival under adverse conditions. BoNT intoxication induces flaccid paralysis, and both natural and synthetic neurotoxins disrupt neuronal communication by targeting synaptic components. However, BoNTs differ in their origin, mechanism of action, structure, and interactions. Clinical harnessing of non-poisoning low doses of BoNT/A and BoNT/B serotypes is used for alleviating symptoms of diverse diseases. Molecular engineering and clinical formulation enabled BoNTs optimization into pharmacologically safe and targeted therapeutic agents that replicate the selective neuronal silencing observed in their natural forms.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773797","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}

{"title":"Early Life Social Isolation Dysregulates Social Reward Processing, BDNF Signaling, and Intracellular Vesicular Sorting in the Nucleus Accumbens of Male and Female Rats","authors":"M. Di Trapano,&nbsp;V. Buzzelli,&nbsp;B. Rizzi,&nbsp;F. Mottarlini,&nbsp;S. Schiavi,&nbsp;R. Ciccocioppo,&nbsp;L. Fattore,&nbsp;P. Romualdi,&nbsp;F. Fumagalli,&nbsp;V. Trezza,&nbsp;L. Caffino,&nbsp;A. Manduca","doi":"10.1111/jnc.70181","DOIUrl":"https://doi.org/10.1111/jnc.70181","url":null,"abstract":"<p>Early-life social deprivation negatively impacts brain development and behavior, increasing susceptibility to neuropsychiatric disorders. In social species such as rats, interactions with the mother and conspecifics are crucial for offspring survival and proper neurobehavioral maturation. However, the mechanisms underlying sex-dependent vulnerability to early-life social stressors, such as social isolation, remain unclear. This study aimed to (i) investigate the effects of early-life social isolation (ESI) on social and depressive-like behaviors in female and male rats during adolescence and adulthood and (ii) explore the molecular mechanisms involved, focusing on the BDNF system in the nucleus accumbens (NAc), a key brain region for social behavior and reward processing. To this aim, we implemented an ESI protocol involving brief periods of repeated social isolation from postnatal day (PND) 14–21 to mimic an adverse early social environment, and then we tested female and male rats across development (i.e., during adolescence and adulthood). Our findings revealed that ESI impaired social reward processing in male rats, whereas general social and depressive-like behaviors remained unaffected in both sexes. These behavioral deficits were accompanied by sex-dependent effects on the BDNF/TrkB signaling pathway in the NAc. Specifically, males exhibited a persistent ESI-induced downregulation of BDNF signaling paralleled by alterations in endocytic-recycling mechanisms mediated by Rab5-Rab11, suggesting increased TrkB sorting and reduced neuroplasticity. Conversely, females showed increased BDNF signaling and enhanced early endosome-recycling mechanisms. These results suggest that male and female rats rely on distinct neurobiological mechanisms to modulate reward processing in response to early-life stress. Overall, our study highlights sex-specific, long-lasting effects of ESI on social reward processing and molecular pathways, providing insight into differential susceptibility to social adversity.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70181","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773810","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}

{"title":"Prenatal Valproate Exposure Affects Cortical Neurite Branching, GABAergic Markers, Motor Reflexes and Ultrasonic Vocalizations in the Male Rat Pups","authors":"Denisa Mihalj,&nbsp;Kristof Laszlo,&nbsp;Tomas Havranek,&nbsp;David Voros,&nbsp;Kristina Kupkova,&nbsp;Zuzana Bacova,&nbsp;Jan Bakos","doi":"10.1111/jnc.70184","DOIUrl":"https://doi.org/10.1111/jnc.70184","url":null,"abstract":"<div>\u0000 \u0000 <p>Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, characterized by early-onset deficits in social interactions, communication, and repetitive behaviors. Dysfunction of gamma-aminobutyric acid (GABA) neurotransmission during neural development has been implicated as a potential mechanism, particularly within the frontal cortex. This study aimed to investigate the effects of prenatal valproate (VPA) exposure on the sensorimotor reflexes, ultrasonic vocalization (USV), and GABAergic markers in the frontal cortex of male offspring. The morphology of primary cortical neurons isolated from control and prenatally VPA-exposed rats was also assessed. Significant sensorimotor developmental delays were observed in VPA-exposed male rats, evident from delays in negative geotaxis and righting reflex tests on postnatal Day 5. The recordings of USV calls showed significant decreases in both the total number of calls and average call duration. Increased gene expression of glutamate decarboxylase 2 (<i>Gad65</i>), vesicular GABA transporter (<i>Vgat</i>), GABAA receptor β subunit 1 (<i>Gabrb1</i>), and Gabarap-like protein 1 (<i>Gabarapl1</i>) was found in the frontal cortex of VPA-exposed pups, indicating alterations in the GABAergic system. Total primary cortical neurons and parvalbumin-positive neurons from VPA-exposed pups showed reduced branching and shorter neurites, whereas GABAergic neurons exhibited increased arborization, and somatostatin-positive neurons showed no change. These findings suggest that prenatal VPA exposure alters cortical neuron morphology and GABAergic markers, potentially contributing to motor and early vocal communication impairments, which may explain the etiology of specific autistic symptoms.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared Mechanisms in Dementia and Depression: The Modulatory Role of Physical Exercise","authors":"Pedro Borges de Souza,&nbsp;Ana Lúcia S. Rodrigues,&nbsp;Fernanda G. De Felice","doi":"10.1111/jnc.70185","DOIUrl":"https://doi.org/10.1111/jnc.70185","url":null,"abstract":"<p>Dementia and depression are two prevalent disorders that warrant significant attention due to their high prevalence and substantial contribution to the global burden of disease. Depression has a high incidence in the elderly and is considered a risk factor for the development of dementia, being a promising target for dementia prevention strategies. Additionally, dementia and depression share common mechanisms through which they manifest pathologically. This review addresses the potential shared mechanisms between dementia and depression, including hypothalamic–pituitary–adrenal (HPA) axis dysfunction, brain atrophy (mainly hippocampus and prefrontal cortex), cognitive decline, and neuroinflammation. It also explores the therapeutic potential of physical exercise in modulating these shared pathways, highlighting its role as a non-pharmacological intervention for the treatment and prevention of both disorders. The review also explores the muscle–brain crosstalk and the intracellular pathways through which physical exercise exerts its effects.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144767280","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}

{"title":"5-HT6 Receptor Inverse Agonists Modulate Diabetic Neuropathic Pain in Female Rats: Evidence for 5-HT6 Receptor Constitutive Activity","authors":"Nazarine Mokhtar,&nbsp;Marcin Drop,&nbsp;Lauriane Delay,&nbsp;Lusliany Josefina Rondón,&nbsp;Lorine Costerousse,&nbsp;Eric Chapuy,&nbsp;Laetitia Prival,&nbsp;Frédéric Lamaty,&nbsp;Xavier Bantreil,&nbsp;Vittorio Canale,&nbsp;Philippe Marin,&nbsp;Pawel Zajdel,&nbsp;Stéphane Doly,&nbsp;Christine Courteix","doi":"10.1111/jnc.70179","DOIUrl":"https://doi.org/10.1111/jnc.70179","url":null,"abstract":"<div>\u0000 \u0000 <p>Painful neuropathy is one of the most common complications of diabetes. First-line therapeutic agents such as tricyclic antidepressants, dual serotonin/noradrenaline reuptake inhibitors, and alpha2-delta ligands of calcium channels (i.e., gabapentinoids) are poorly effective. New strategies targeting the serotonin type 6 receptor (5-HT₆R) and mechanistic Target Of Rapamycin (mTOR) signaling have recently emerged. Until a few years ago, preclinical studies of pain in rodents were more often carried out in males than in females, despite compelling evidence of sex-specific mechanisms in pain. Here, we investigated the role of 5−HT₆R/mTOR signaling in neuropathic pain in streptozocin (STZ)-induced type 1 diabetes (T1D) in female rats. Mechanical hyperalgesia was attenuated in female diabetic (STZ-D) rats by systemic injection of 5-HT₆-R inverse agonists. Further, administration of full (PZ-1386, SB258585) but not partial (PZ-1179) 5−HT₆R inverse agonists alleviated cognitive deficits in female STZ-D rats. Intrathecal administration of the mTOR inhibitor rapamycin or a cell-penetrating peptide that disrupts the physical interaction between the 5-HT₆R and mTOR also reduced pain and cognitive comorbidity in females. Together with previous data obtained in STZ-D male rats and in spinal nerve ligation (SNL) and oxaliplatin (OXA) models of neuropathic pain, these results suggest that the analgesic and procognitive effects of 5-HT₆R inverse agonists are sex-specific and dependent on the etiology of neuropathic pain, highlighting the importance of personalizing treatment that considers the patient's sex, etiology of neuropathy, and the presence or absence of comorbid cognitive symptoms.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144767281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vivo Cortical Microstructure: Relationships With Tauopathy and Cognitive Impairment in the Elderly","authors":"Christin Schifani,&nbsp;John A. E. Anderson,&nbsp;Arash Nazeri,&nbsp;Aristotle N. Voineskos,&nbsp;the Alzheimer's Disease Neuroimaging Initiative","doi":"10.1111/jnc.70167","DOIUrl":"https://doi.org/10.1111/jnc.70167","url":null,"abstract":"<p>Positron Emission Tomography (PET) of tau is considered “the” indicator of Alzheimer's pathology. However, non-PET proxies would be helpful for wider accessibility. We used Neurite Orientation Dispersion and Density Imaging (NODDI)-derived indices (i.e., orientation dispersion [ODI], neurite density [NDI], and free-water [fISO]) to determine relationships of gray matter microstructure with tau and cognitive impairment. We assessed the fit between NODDI indices, cortical thickness/subcortical volume (CT/ScVol), and tau via multiple factor analysis (MFA) using data from 80 participants from the ADNI-3 dataset with overlapping multishell diffusion-weighted and tau-PET scans ([¹⁸F]AV-1451); 49 were considered cognitively normal older adults (age ~74 years), 26 were diagnosed with mild cognitive impairment (age ~75 years), and five had Alzheimer's dementia (age ~78 years). fISO and tau shared a large amount of spatial overlap, and both strongly correlated with the first MFA dimension. Macrostructural features (i.e., CT/ScVol) were 7% less related to this first MFA dimension than fISO and 8% less than tau. Subsequent mediation analyses demonstrated that fISO mediated the relationship between CT/ScVol and tau, explaining all of the variance. Our results suggest that microstructural features derived from NODDI such as fISO might be useful adjunct markers to tau, which needs to be confirmed in longitudinal studies. Cortical fISO, rather than macrostructure (i.e., CT/ScVol), may represent tau's impact on the brain (and, by extension, cognition).</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758669","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}

{"title":"Adiphenine Alleviates Impulsive-Like Behaviors in Aged Mice by Inhibiting Nicotinic Acetylcholine Receptors.","authors":"Heng-Yue Peng, Yi-Long Gao, Lu-Ying Wang, Jin-Meng Lv, Hui-Tao Miao, Liang-Ya Li, Rong-Xin Song, Ting-Ting Zhou, Ping An, Xiao-Chun Zhao, Li-Min Zhang","doi":"10.1111/jnc.70190","DOIUrl":"https://doi.org/10.1111/jnc.70190","url":null,"abstract":"<p><p>Postoperative neurocognitive disorders (PND) are prevalent complications in the elderly following surgical interventions and anesthesia, with the underlying protective and damaging mechanisms remaining largely elusive. Impulsive-like behaviors and a decline in cognitive function were observed in the mouse model of PND established through tibial fracture surgery, accompanied by increased activity of astrocytes in the hippocampal CA1 region. Additionally, transcriptome sequencing revealed increased expression of nicotinic acetylcholine receptors (nAChRs) in PND. In this study, we aimed to investigate the role of nAChRs in the pathogenesis of PND in aging mice. In 18-month-old male C57BL/6 mice, a PND model was established by tibial fracture surgery, and brain tissues were collected for transcriptomic sequencing 24 h post-surgery. Behavioral assessments of PND mice were conducted using open field, light-dark box, and fear conditioning tests. An nAChRs inhibitor, Adiphenine (125 nM per day), was administered daily for 7 days via intracerebroventricular microinfusion. Pathological changes were observed using immunofluorescence staining and Western blotting, and hippocampal CA1 spikes activity and local field potentials (LFP) were monitored with a microelectrode array. Transcriptomic sequencing of the brains of PND mice revealed upregulation of Cholinergic Receptor Nicotinic Beta 2 Subunit (Chrnb2) and Cholinergic Receptor Nicotinic Beta 4 Subunit (Chrnb4). Additionally, there was an increase in neuronal spikes and enhanced LFP power in the hippocampal CA1 region, along with an increase in the number and morphological changes of astrocytes. Adiphenine was able to inhibit tibial surgery-induced impulsive-like behaviors, but it showed no significant improvement in cognitive function. It also reduced spikes firing and LFP power in the CA1 region. Our study revealed that anesthesia and surgery-induced PND models exhibit impulsive-like behaviors and cognitive impairment. Astrocyte activation and elevated Vglut1 expression may be contributing factors, with nAChRs likely playing an initiating role in this process. Adiphenine can improve impulsive-like behaviors by inhibiting nAChRs.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 8","pages":"e70190"},"PeriodicalIF":4.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}