Aging is characterized by progressive deterioration in cellular function and molecular integrity, which in turn increases vulnerability to age-related diseases, such as neurodegenerative disorders. Cellular senescence is a hallmark of biological aging that plays a crucial role in the development of neurodegenerative diseases. Cellular autophagy, a lysosome-mediated process of degradation, is crucial for maintaining cellular homeostasis and longevity. Nutritional strategies, such as intermittent fasting (IF), which consist of cycles of fasting and normal feeding, have been recognized as potential methods to induce autophagy and derive health benefits. Autophagy is crucial for the degradation of sequestered proteins and damaged organelles, thus maintaining cellular vigor and balance. However, with increasing age, autophagy is compromised, suggesting the need for a stable or optimal rate of autophagy for the maintenance of cellular uptake. IF has the potential to modulate the process of autophagy by inducing changes in ATP and ADP levels during fasting through the activation of pathways such as the AMPK and Sirtuin 1 pathways, which promote the activation of autophagosome formation while simultaneously inhibiting mTOR, an inhibitor of autophagy. Despite the encouraging properties of the IF, there are constraints, as responses may vary incredibly among subjects, and the ideal duration of fasting is uncertain. Furthermore, the potential for new metabolic diseases associated with IF is not fully understood. Understanding the intricate relationships among aging, autophagy, and dietary restrictions such as intermittent fasting could pave the way for novel therapeutic strategies to increase longevity and mitigate age-related health issues. Brain aging is associated with various hallmarks leading to neurodegenerative diseases and impaired autophagy, causing the accumulation of senescent cells. Intermittent fasting, a dietary regimen, controls food intake by alternating between eating and fasting. It regulates various pathways that facilitate autophagy activation and senescent cells clearance in the brain [Image: see text]
Cerebral ischemia-reperfusion (I/R) injury triggers a cascade of neuroinflammatory responses and multiple forms of regulated cell death. PANoptosis, integrating pyroptosis, apoptosis, and necroptosis, has been implicated in inflammatory disorders, but its role in cerebral I/R remains unclear. This study explored the molecular profile and immune relevance of PANoptosis-related genes (PRGs) in rat I/R injury. A rat I/R model was established by transient middle cerebral artery occlusion (MCAO). Transcriptome sequencing identified differentially expressed genes (DEGs) using DESeq2, and PANoptosis-related DEGs (PR-DEGs) were obtained by intersecting with GeneCards-derived PRGs. Functional enrichment (GO, KEGG, Metascape, GSEA), weighted gene co-expression network analysis (WGCNA), and immune infiltration analyses were performed to uncover biological functions and immune features associated with PR-DEGs. Rats subjected to I/R injury showed significant infarction, neurological deficits, and increased TNF-α, IL-1β, and IL-10 expression, along with downregulated Bcl-2 and upregulated CD16 and iNOS, indicating strong inflammatory responses. A total of 51 PR-DEGs were identified, primarily enriched in inflammatory and immune signaling pathways such as TNF, NF-κB, and MAPK. WGCNA revealed the salmon module as most correlated with I/R injury, and hub genes including CASP8, STAT3 were identified. Correlation and immune infiltration analyses demonstrated strong associations between key PR-DEGs and pro-inflammatory immune cells, suggesting a close relationship between PANoptosis-associated gene expression patterns and immune dysregulation in I/R injury. Our findings suggest coordinated activation of PANoptosis-related signaling in cerebral I/R injury. CASP8 and STAT3 were identified as key PR-DEGs associated with I/R, providing a foundation for further mechanistic investigation.
Protein homeostasis is a critical aspect of cellular homeostasis as proteins are one of the most diverse biomolecules, responsible for multiple molecular and cellular functions. Protein quality control machinery is essential for maintaining integrity of cellular proteome via regulating its synthesis, structure, function, and degradation. Molecular chaperones are central to the protein quality control apparatus of cells and assist in folding nascent polypeptides, maturation, sequestration, solubilisation, and degradation of proteins. The coordination and cooperation between multiple cellular chaperones and other quality control elements, such as ubiquitin-proteasome system and autophagy, form a network, critical for proteostasis. Disturbed proteostasis and protein aggregation are hallmark features of neurodegenerative diseases. Re-establishing cellular proteostasis and enhancing chaperones' levels and functions can alleviate protein aggregation and associated cytotoxicity. Here, we have explored the potential of abundant cellular chaperone Hsp90, large chaperone Hsp110, small chaperone Hsp27, and anti-oxidant and mitoprotective chaperone DJ-1 in the regulation of proteostasis, with implications for neurodegenerative diseases, Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. We have focused on roles and mechanisms of function of these chaperones in countering disturbed proteostasis in neurodegenerative disorders.
This study aims to explore the role and underlying correlation of miR-941 in the targeted regulation of the Keap1/Nrf2 signaling pathway in the prognosis of senile ischemic stroke (IS), providing new targets and strategies for clinical treatment. Totally 102 elderly IS patients admitted from July 2022 to June 2023 in Jing'an District Shibei hospital were enrolled and divided into hyperacute, acute, subacute, and chronic phases by disease course and imaging results. Peripheral blood samples were collected. RT-PCR was used to detect miR-941, Nrf2 mRNA and Keap1 mRNA expression levels, and ELISA for HO-1, NQO-1, SOD, and GSH-Px1 expression. The modified Rankin scale (mRS) evaluated patients' prognosis, and logistic regression analyzed influencing factors. The receiver operating characteristic (ROC) and Kaplan-Meier curves analyzed the predictive value of miR-941 and the Nrf2/Keap1 signaling pathway in IS prognosis and their correlation with patients' survival periods. The expression levels of miR-941 and Nrf2 mRNA gradually decreased in different stages of IS, while the expression of Keap1 mRNA gradually increased, and the expression levels of antioxidant factors HO-1, NQO-1, SOD, and GSH-Px1 also decreased significantly (all P < 0.001). The relative abundances of miR-941 and Nrf2 mRNA were significantly negatively correlated with the NIHSS score (P < 0.001), while Keap1 mRNA was positively correlated with the NIHSS score (P < 0.001). Logistic regression analysis showed that miR-941 and Nrf2 mRNA were protective factors for a good prognosis of IS (P < 0.001), while Keap1 mRNA was a risk factor for a poor prognosis (P < 0.01). ROC curve analysis showed that miR-941 had high predictive efficacy in the prognosis of IS (the AUCs were 0.801). Kaplan-Meier survival analysis showed that the survival periods of patients in the high-expression groups of miR-941 and Nrf2 were significantly longer than those in the low-expression groups (P < 0.001), while the survival period of patients in the high-expression group of Keap1 mRNA was significantly shortened (P < 0.001). The correlation between miR-941 and Keap1/Nrf2 signaling pathway is crucial in the course and prognosis of senile ischemic cerebral infarction. High miR-941 and Nrf2 mRNA levels correlate with good prognosis, while high Keap1 mRNA levels link to poor prognosis. These molecules probably serve as potential biomarkers for clinical prognosis and new treatment targets.
A healthy lifestyle, characterized by moderate physical activity, appropriate caloric intake, and a diet rich in fruits and vegetables, contributes to maintaining overall health and preventing several degenerative diseases. Within this context, the health of the muscular system also plays a pivotal role. Increasing evidence highlights the importance of a balanced diet, in combination with regular physical exercise, in preserving muscle function and integrity. Polyphenols, present in fruits, vegetables, and plant-derived foods, have emerged as key allies in counteracting oxidative stress and inflammation, processes that affect muscle cell health. These compounds are involved in the regulation of muscle cell development and differentiation, as well as in the regeneration processes following injury or excessive physical exertion. Through their ability to modulate reactive oxygen species levels, inflammation, and specific cellular pathways, polyphenols are capable of influencing muscle development and homeostasis. This review provides a comprehensive overview of current knowledge regarding the impact of polyphenols on skeletal muscle growth, development, and maintenance, with a focus on their mechanisms of action and therapeutic potential. Recent and innovative extraction and administration strategies, aimed at overcoming some limitations that normally characterize experimentation with bioactive molecules such as polyphenols, are considered and discussed in a prospective view.
Alzheimer's disease (AD) is a complex neurological ailment that is associated with memory loss, confusion, and mood disturbances. Genetic, molecular, and cellular factors, including oxidative stress, inflammation, neurotransmitter alterations, and amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), are associated with the disease. These can be associated with protein and DNA damage, mitochondrial dysfunction, energy shortages, inflammation, and hippocampal neuron death. Circular non-coding RNAs (circRNAs) are covalently closed and essential to many physiological and pathological processes. CircRNA may be a molecular modulator of neurodegeneration, as it may influence protein transcription and interaction with essential RNA-binding proteins (RBP) in the cortical and hippocampal regions, particularly in photoreceptor neurons and white matter.Insulin-like Growth Factor 2 mRNA-Binding Protein 3. (IGF2BP3), which belongs totheinsulin-like growth factor 2 encoded mRNA-binding protein family, affects neuronal differentiation, synaptic plasticity, translation, localization, mRNA stability, and neurogenesis. Research indicates that IGF2BP3 has been reported to modulate neuron survival and function genes, as well as BACE1 translation, which creates Aβ. AD has a complex etiology; thus, understanding its molecular processes is crucial. Investigating circRNAs and IGF2BP3 activities may reveal new disease are associated with and therapy options. This review explores the emerging roles ofcircRNAs as diagnostic biomarkers and potential therapeutic targets inmanagingAD.
Intracerebral hemorrhage (ICH) is a prevalent cerebrovascular disease, which is an important cause of death and disability. Accumulating evidence indicates that the neutrophil extracellular traps (NETs) and complement cascade play an important role in the injury after ICH. Neutrophils, the first leukocyte subset recruited to the cerebral parenchyma following ICH, exacerbate cerebral tissue damage via the release of NETs. As a core component of the innate immune system, the complement system aggravates cerebral edema and pathological injury after ICH through a variety of complex pathological processes. Some complement molecules, such as C5a, C3a, and C1q, are associated with increased neutrophil recruitment and NETs release. Therefore, this review summarized the formation of NETs and activation of complement, the role of NETs and complement in ICH, the interaction between NETs and complement, and related treatment methods, providing new therapeutic strategies for clinical treatment.
Chronic stress induces detrimental effects on cognition, behavior, and hippocampal integrity. An enriched environment (EE) has been shown to enhance learning and memory; however, its role against chronic immobilization stress (CIS)-induced alterations and the underlying mechanisms remain insufficiently explored. This study aimed to investigate the protective effects of EE on CIS-induced behavioral, molecular, and structural changes in the hippocampus of adult male rats. Thirty-two adult male Wistar albino rats were assigned to four groups: control, control + EE, CIS, and CIS + EE. Rats were subjected to CIS (4 h/day) followed by EE exposure (2 h/day) for 28 days. Behavioral assessments were conducted. Serum corticosterone levels, hippocampal brain-derived neurotrophic factor (BDNF), and mRNA expression of aquaporin-4 (AQP4) and glutamate receptors (GluA1 and GluA2) were evaluated. Histopathological, ultrastructural, and immunohistochemical (LC3) examinations were performed. EE significantly ameliorated CIS-induced cognitive and behavioral impairments and restored hippocampal histological and ultrastructural integrity. These effects were associated with reduced serum corticosterone levels, increased hippocampal BDNF levels, and upregulated expression of AQP4, GluA1, and GluA2 mRNA. These findings suggest that EE is a promising non-pharmacological strategy for mitigating stress-induced hippocampal dysfunction and cognitive decline.
Glioblastoma (GB), the most aggressive primary brain tumor, is characterized by profound inter- and intratumoral heterogeneity and a highly immunosuppressive tumor microenvironment (TME), both of which contribute to its poor prognosis and resistance to conventional therapies. The dynamic interplay between malignant cells and diverse TME constituents including immune cells, neural elements, and extracellular matrix components drives tumor progression, clonal evolution, and therapeutic failure. Traditional treatment modalities such as surgery, radiotherapy, and chemotherapy often fall short due to their inability to address the spatial and temporal complexity of the TME. Recent advances in artificial intelligence (AI) and cellular MRI profiling offer promising avenues for decoding the GB microenvironment at unprecedented resolution. By integrating AI-driven analysis of cellular MRI signatures, researchers can identify distinct microenvironmental niches and resistant subclones, enabling the development of targeted therapies that simultaneously disrupt tumor cells and their supportive ecosystems. This approach holds potential to overcome current therapeutic limitations and pave the way for personalized, microenvironment-informed interventions in GB management.
Plasma phosphorylated tau217 (p-tau217) is a promising biomarker for Alzheimer's disease (AD) risk detection. Its relationship with brain microstructure and cognitive impairment remains unclear. Multi-component T2-relaxometry is an MRI technique sensitive to myelin content, axonal degeneration, and neuroinflammation. A total of 229 participants classified by p-tau217 levels into p-tau217- (n = 176), p-tau217+ (n = 26), and intermediate (n = 27) underwent neuropsychological testing and MRI. Voxel-wise general linear models controlling for age, sex, education, apolipoprotein E (APOE, and white matter lesions were performed for total water content (TWC), myelin water fraction (MWF), intra-/extracellular water fraction (IEWF), geometric mean of intra-/extracellular water (T2IE), and free/quasi-free water fraction (FQFWF). The p-tau217+ participants showed poorer cognition, increases in FQFWF and TWC, and reductions in IEWF and T2IE across cortical and subcortical regions and white matter tracts. High p-tau217 level associates with brain microstructure alterations and poorer cognition, supporting it as a biomarker of AD-related neuropathology and the utility of T2-relaxometry for detecting tissue integrity.
Central nervous system (CNS) development commences in third week of gestation with neural stem cells (NSCs), which, through symmetric division, expand the pool of stem cells and generate diverse types of neuronal and glia cells of CNS via asymmetric division. During neurodevelopment, spatiotemporal coordination is fundamental for appropriate morphogenesis and producing neuronal connections. Besides gene regulatory networks, external and internal factors guide NSCs during self-renewal, fate determination and differentiation. Recent studies indicate metabolism as one of the common converging integrators in NSCs to trigger modifications in response to external factors. One such external factor is micronutrients that profoundly affect different stages of neurodevelopment, including, differentiation, neural migration and maturation. This review aims to provide a summary of recent insights into how metabolism and micronutrients regulate different events of neurodevelopment including proliferation, fate determination and differentiation. Notably, we focus on illustrating the implications of mitochondria as key determinants of NSC fate and functionality. We also highlight the recent development on how metabolism orchestrates the epigenome of NSCs during proliferation and differentiation. We further explore the role of nutraceuticals in mitigating the risk of neurodevelopmental and adult neurological disorders, highlighting recent innovations in their therapeutic applications. An in-depth grasp of these molecular processes is fundamental to improving translational strategies for treating neurological disorders.
Despite advances in acute ischemic stroke (AIS) research, identifying reliable biomarkers and regulatory mechanisms remains challenging. We first identified AIS-related genes via extensive literature review, retrieved dataset GSE16561 from the Gene Expression Omnibus (GEO, https://ncbi.nlm.nih.gov/geo/), and performed differential/enrichment analyses. Bioinformatics verified N6-methyladenosine (m6A) sites in target genes, focusing on the methyltransferase-like protein 14 (METTL14)/growth arrest and DNA damage-inducible β (GADD45B) m6A methylation/brain-derived neurotrophic factor (BDNF) axis. Peripheral blood samples, biochemical indicators, and demographic data were collected from Hongqi Hospital Affiliated to Mudanjiang Medical University. Human umbilical vein endothelial cells (HUVECs) underwent transfection and oxygen-glucose deprivation (OGD). METTL14, GADD45B, and BDNF were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR); BDNF protein by enzyme-linked immunosorbent assay (ELISA); global RNA m6A by Dot Blot; and GADD45B m6A by methylated RNA immunoprecipitation-quantitative polymerase chain reaction (MeRIP-RT-qPCR). Differential, diagnostic efficacy, logistic regression analyses, and nomogram validation were conducted. AIS patients showed increased METTL14, decreased GADD45B/BDNF, and increased levels of global m6A RNA and GADD45B m6A RNA (P < 0.05). Receiver operating characteristic (ROC) analysis confirmed the three genes' good diagnostic efficacy. The nomogram integrating these genes, globulin (GLOB), diabetes, high-density lipoprotein cholesterol (HDL-C), and hypertension performed excellently. This study highlights METTL14, GADD45B, and BDNF as key AIS biomarkers; METTL14 may indirectly regulate BDNF via GADD45B m6A methylation, providing potential therapeutic targets and novel mechanistic insights.
Growing evidence underscores neuroinflammation's role in Parkinson's disease (PD), with accumulating evidence suggesting a potential role for peripheral inflammation. The clinical applicability and mechanistic relevance of peripheral inflammatory biomarkers in PD remain to be fully elucidated. We analyzed data from the Parkinson's Progression Markers Initiative (PPMI), including longitudinal clinical assessments, blood counts, cerebrospinal fluid (CSF) biomarkers, and genetic data. Six peripheral inflammatory indices were derived: neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI). Spearman correlation, multiple linear regression, and generalized estimating equations were employed to examine associations. Unsupervised k-means clustering was performed to identify distinct inflammatory clusters, with differences assessed using ANCOVA analysis. NLR and SII were significantly elevated in PD, with NLR showing the strongest association. Peripheral inflammatory biomarkers showed distinct clinical correlations, with NLR demonstrating associations with both non-motor (cognitive decline, olfactory impairment, and depression, p < 0.001) and motor symptoms (p < 0.001). SII, and SIRI showed correlations with motor progression (p < 0.001), while SII additionally associated with sleepiness disorders (p < 0.001). Cluster analysis identified two distinct inflammatory clusters: a high-inflammation cluster demonstrating significantly worse cognitive function (p = 0.008), olfactory impairment (p < 0.001), and autonomic dysfunction (p < 0.001) at baseline, along with accelerated motor (p = 0.038) and cognitive decline (p < 0.001) during follow-up. This high-inflammation cluster also showed elevated CSF neurodegeneration markers including pTau, tTau, NfL, and GFAP (p < 0.05). Peripheral inflammatory biomarkers show robust associations with clinical features in PD, highlighting their potential as markers associated with disease features and progression, and suggesting a basis for inflammatory-based subgrouping.
Neurosteroids play a significant role in brain functions with substantial implications for mood regulation, seizure susceptibility, stress response, and potential therapeutic applications. However, dysregulation of steroidogenesis and its signalling is associated with various neurological and psychiatric disorders, such as major depressive disorder, schizophrenia, tourette syndrome and post-traumatic stress disorder, with altered levels of neuroactive steroids contributing to these conditions. Neurosteroids can counteract the effects of stress by enhancing GABAergic inhibition, thereby helping to maintain emotional homeostasis. Furthermore, neuroinflammatory processes linked to neurodegenerative diseases, including Alzheimer's and Parkinson's, can disrupt neurosteroid synthesis. The potential for therapeutic modulation of neurosteroid biosynthesis via ligands targeting steroidogenic pathways offers an exciting avenue for treatment. Despite the promise of neuroactive steroids, their rapid metabolism and low oral bioavailability pose significant challenges. Consequently, extensive research is now focused on developing synthetic analogues and modulators that can modulate neuroactive steroid synthesis and metabolism. This review is based on an understanding of neuroactive steroids and their role in neurological disorders.
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has recently emerged as an important regulator of musculoskeletal development. Inhibition of the pathway with small-molecule JAK inhibitors (jakinibs) may improve tendon development and healing. The goal of the present study was to characterize the effects of blocking JAK1 and 2 during a key postnatal musculoskeletal growth phase in Sprague-Dawley rats (postnatal day (PND) 7-28). We administered vehicle or baricitinib via chow (3 mg, or 10 mg/kg BW/day), which blocks JAK1 and JAK2, for 21 days and characterized the resulting systemic and musculoskeletal effects. We found a striking reduction in overall growth of the juvenile rats with baricitinib treatment, with a reduction in body weight of ∼30% for males and ∼20% for females at PND 28. The spleen was smaller in size with baricitinib treatment, even after normalization to body weight. Bone and tendon similarly showed decreases in mechanical properties without dramatic changes in material properties. Consistent with the role of JAK2 in growth hormone signaling, circulating IGF-1 levels were ∼65% lower in animals fed baricitinib. Our findings suggest that oral administration of baricitinib impairs postnatal growth and development in juvenile rats, likely through the GH/JAK2/IGF-1 axis. The clinical translation of these preclinical data and potential for similar adverse clinical effects of baricitinib in pediatric subjects is unknown. Baricitinib could provide effective treatment for acromegaly, but clinicians should be cautioned of this potential side effect and strongly consider using alternative treatments in children who have yet to reach full size.
Parkinson’s disease (PD) is characterised by progressive dopaminergic neurodegeneration, alpha-synuclein (α-syn) aggregation, and neuroinflammation. Clinical and experimental studies suggest that sex influences disease onset, progression, and treatment response, yet its impact on α-syn-mediated pathology remains incompletely understood. In this study, we investigated sex-dependent progression of behavioural and neuropathological alterations in a mouse model overexpressing A53T α-syn. Male and female C57BL/6J mice received bilateral intranigral injections of adeno-associated viral vectors encoding mutant A53T α-syn or empty vectors. Motor performance was assessed at 60 and 120 days post-surgery using open field, wire hang, pole, and balance beam tasks complemented by automated behavioural analysis (DeepLabCut, SimBA). Brains were processed for immunohistochemical evaluation of α-syn accumulation, tyrosine hydroxylase (TH) expression, axonal integrity, and glial activation. A53T α-syn overexpression induced early subtle motor deficits primarily in males, accompanied by increased immobility on the balance beam despite preserved substantia nigra compacta neuron counts. By 120 days, striatal TH immunoreactivity was markedly reduced in α-syn mice. An integrated axonal degeneration index, combining TH optical density and swelling counts, revealed a faster progression of striatal axonopathy in males. Both sexes showed enhanced striatal astrogliosis, indicating α-syn-driven neuroinflammation independent of sex. These findings identify early axonal degeneration and reactive astrogliosis as key pathological events preceding neuronal loss in A53T α-syn mice. Importantly, the pronounced male vulnerability highlights sex as a critical biological variable in modelling PD progression and in developing precision-based neuroprotective strategies. [Image: see text] The online version contains supplementary material available at 10.1007/s10571-026-01707-9.
The formation of filopodia and podosome-like structures as a part of the Alzheimer's disease pathology has been examined over the recent past. Podosomes are structures rich in F-actin, which are involved in adhesion and mechanosensing. To assist the podosomes in its roles, it has an advanced and dynamic structure, comprised of actin filaments as a part of its core, the ring region composed of integrin and integrin-actin linkers and the cap composed of tropomyosin 4. The podosomes organize from clusters to rings to belts. Various components are involved in the formation of podosomes, including phosphatidylinositol, Src kinases, PI3 kinase, the adaptor TKS5, integrins, cortactin, paxillin, Iba1, Sk3, PAM, EB1, CDC42, WASP and Arp2/3. Podosomes play a role in cell adhesion by attaching cells to the ECM, while also contributing to the latter's degradation. Many studies have also shown that podosomes and invadosomes are involved in pathogen clearance. Various factors responsible for the formation of podosomes have also been linked to the Alzheimer's disease, including TKS5 and ADAM12 which have been liked to Amyloid-β. TKS5 and Arp2 are involved in the interactions between the P2Y12 receptor and Tau, which lead to the formation of podosomes. It is suggested that these podosomes are involved in the microglial migratory process.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by repetitive behaviors, communication deficits, and frequent comorbidities. While both genetic and environmental factors contribute to ASD etiology, immune dysregulation has emerged as a potential environmental driver, suggesting a critical role of chronic inflammation in ASD pathophysiology. We previously demonstrated that ASD individuals display specific changes in plasma EV cargo which is associated with immune dysregulation. Here, we show that ASD EVs contain dysregulated cytokine profiles, including Gro-α/CXCL1, RANTES/CCL5, IFN-γ, stem cell growth factor beta (SCGF-β), and IL-15. Notably, ASD EVs enhance IFN-γ secretion from peripheral blood lymphocytes (PBLs) in direct co-cultures, which can be reversed by treatment with the anti-inflammatory agent dexamethasone (Dex). Our findings suggest that ASD EVs contribute to chronic inflammation and highlight a potential therapeutic target for ASD intervention by mitigating ASD EV-induced chronic inflammation. The online version contains supplementary material available at 10.1007/s10571-026-01723-9.
Animals learn and adapt to environmental changes. However, neural plasticity can also become maladaptive, leading to neurological and psychiatric disorders. How do we use known molecular mechanisms to harness the power of neural plasticity to prevent and treat diseases? Consolidating learning is known to require new protein synthesis. We found that mRNA m6A modifications and the RNA-binding protein YTHDF1 are required for molecular, cellular, and behavioral adaptations in response to environmental changes. Deletion of Ythdf1 in dopamine D1- or D2 receptor-expressing neurons selectively impaired D1- or D2-dependent learning, respectively, including both adaptive and maladaptive learning. This highlights YTHDF1 as a potential therapeutic target for preventing pathological plasticity. YTHDF1 recognizes m6A modifications on transcripts and regulates their translation. Elevated cAMP triggered increased protein synthesis in control striatal neurons but not in Ythdf1-deficient neurons. Behaviorally, cell-type-specific Ythdf1 deletion resembled learning phenotypes caused by deletion of the m6A methyltransferase gene Mettl14, suggesting YTHDF1 as the main mediator of m6A-dependent regulation in the striatum.
Stroke is one of the leading causes of mortality and disability worldwide, with ischemic stroke accounting for over 87% of all stroke cases. Chronic kidney disease (CKD) is one of the major risk factors for stroke, as CKD patients have shown evidence of impaired cerebral autoregulation leading to exacerbated stroke pathology. The worsening of stroke outcomes in CKD patients is limitedly understood. Inflammation plays a pivotal role in driving the CKD-stroke pathology. The cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon gene) pathway acts as a key mediator of inflammation in both pathologies. As mitochondrial dysfunction plays a common connecting link between stroke and CKD, activation of the innate-immune response mediated by cGAS-STING pathway becomes inevitable. Therefore, it becomes imperative to understand the role of mitochondria in the exacerbation of stroke outcomes following CKD. In addition, the critical role of altered immune response leading to exacerbated mitochondrial dysfunction and aging in CKD-stroke complex is also crucial to investigate. To study this, CKD was induced in male Sprague Dawley rats followed by middle cerebral artery occlusion (MCAo) to develop a CKD-Stroke complex animal model. Behavioral studies were conducted, and tissues were harvested for biochemical, histological, molecular, mitochondrial and genetic studies. Our findings from transcriptomic and proteomic analyses confirm upregulation of STING, interferons and related genes, alongside downregulation of mitochondrial health markers, in the CKD-stroke complex. This molecular profile reflects accelerated mitochondrial aging due to altered innate immunity mediated by cGAS-STING pathway.