Exp. Neurol. [JOURNAL]
Sun
200 papers
CD4 T cells as a missing mechanistic link in post-hemorrhagic hydrocephalus.
Dhingra S, Vohra HZ, Shumilov K … +5 more , Michenkova M, Limbrick OW, Bos P, Limbrick DD, Garcia-Bonilla M
Exp Neurol · 2026 Jul · PMID 41933713 · Publisher ↗
Post-hemorrhagic hydrocephalus (PHH) is a complex secondary condition that develops from several types of brain bleeds, specifically germinal matrix-intraventricular hemorrhage (GMH-IVH) in neonates, and IVH, aneurysmal...
Post-hemorrhagic hydrocephalus (PHH) is a complex secondary condition that develops from several types of brain bleeds, specifically germinal matrix-intraventricular hemorrhage (GMH-IVH) in neonates, and IVH, aneurysmal subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) in adults. PHH pathophysiology is multifactorial, involving impaired cerebrospinal fluid (CSF) circulation and/or absorption and neuroinflammation. Current management of PHH relies on surgical CSF diversion, which carries high complication rates and does not directly target underlying neuroinflammation. Increasing evidence implicates innate and adaptive immune mechanisms-particularly T cells-as critical drivers of secondary injury. This review synthesizes the role of CD4 T cells in driving the neuroinflammatory cascade, barrier dysfunction, and neural injury across various forms of intracranial hemorrhage including GMH, IVH, ICH, and SAH-ultimately culminating in the development of PHH. By examining CD4 T cell subsets, routes of entry into the brain, derived cytokine release, and the resulting crosstalk with resident neural cells, we elucidate how these immune mediators facilitate the pathogenesis of PHH after both pediatric and adult hemorrhages. It also reviews emerging pharmacologic strategies that modulate T cell trafficking and effector function in similar neurological conditions and highlights key mechanistic gaps and future directions. Understanding how CD4 T cell subsets orchestrate neuroinflammation after a hemorrhage may enable development of targeted, non-surgical therapies to prevent or mitigate the development of PHH.
Research progress on the relationship between mitochondrial dysfunction and inflammatory response in brain cells following traumatic brain injury: A review.
Wang S, Shi L, Tian Y … +3 more , Wu J, Guo F, Yu A
Exp Neurol · 2026 Jul · PMID 41933712 · Publisher ↗
Traumatic brain injury (TBI) initiates a complex secondary injury cascade, within which the bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation forms a self-amplifying vicious cycle, termed th...
Traumatic brain injury (TBI) initiates a complex secondary injury cascade, within which the bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation forms a self-amplifying vicious cycle, termed the "mitochondria-inflammation axis." This axis is increasingly recognized as a core mechanism driving progressive neural damage. Following TBI, impaired mitochondria not only cause bioenergetic failure but also release copious damage-associated molecular patterns (mtDNA, etc.) and reactive oxygen species (ROS), which potently activate innate immune platforms such as the NLRP3 inflammasome and NF-κB signaling. Conversely, the ensuing inflammatory milieu further aggravates mitochondrial damage through oxidative stress and disruption of quality control, creating a feed-forward loop. This review systematically synthesizes recent advances in understanding this axis, highlighting novel concepts like immunometabolic reprogramming of microglia and intercellular mitochondrial transfer. Furthermore, we critically evaluate emerging therapeutic strategies aimed at breaking this cycle, including mitochondria-targeted antioxidants, precise immunomodulators, and pioneering mitochondrial transplantation. By integrating evidence from multi-omics studies and diverse models, this review provides a unified conceptual framework for understanding TBI pathophysiology and illuminates promising avenues for future translational research.
Revealing subcellular retinal alterations in 5xFAD B6SJLF1/J mice.
Giani A, Musi CA, Priori EC … +9 more , Turchetti S, Passi M, Galbiati S, Viganò I, Bakker N, Klaassen I, Zerbini G, Borsello T, RECOGNISED consortium
Exp Neurol · 2026 Jul · PMID 41932564 · Publisher ↗
The 5xFAD mouse model recapitulates key pathological features of Alzheimer's disease (AD). However, it remains unclear whether JNK activation represents a common pathogenic mechanism driving both retinal and cerebral neu...
The 5xFAD mouse model recapitulates key pathological features of Alzheimer's disease (AD). However, it remains unclear whether JNK activation represents a common pathogenic mechanism driving both retinal and cerebral neurodegeneration. Establishing such a shared pathway would significantly enhance the retina's potential as an accessible window into the central nervous system (CNS) for monitoring AD progression. We analyzed total retinal homogenates and postsynaptic-enriched protein fractions from 2, 4, 6, and 10-month-old 5xFAD B6SJLF1/J mice using Western blotting and immunofluorescence staining. Key markers of JNK signaling (JNK, p-JNK, JNK3, c-Jun, p-c-Jun) and synaptic integrity (PSD95, p-PSD95) were examined. Additionally, we assessed gliosis (GFAP) and amyloid pathology (APP, p-APP) to evaluate retinal AD progression. Finally, we compared retinal layer thickness between 5xFAD and wild-type (WT) mice across these age points. Although Western blotting revealed no significant JNK signaling activation in total retinal homogenates, synaptic dysfunction was evident through increased PSD95 phosphorylation in 5xFAD mice. Immunofluorescence analysis demonstrated elevated JNK3 immunoreactivity and gliosis in transgenic animals compared to controls. Notably, while WT mice exhibited age-related inner nuclear layer (INL) thinning, 5xFAD mice maintained stable INL thickness and showed progressive total retinal thickening. These findings demonstrate fundamental differences in AD pathology between retinal and brain tissues in 5xFAD B6SJLF1/J mice. The weak JNK activation signature observed in retinal tissue, contrasting with robust brain pathology, suggests current limitations in developing retinal biomarkers for AD detection. Furthermore, our results underscore the necessity of both technical refinement and cautious cross-species interpretation when evaluating the retina's potential as a CNS disease monitor.
Progressive chronic kidney disease contributes to elevated cell death mechanisms and aggravates post-stroke severity.
Chelluboina B, Mehta SL, Arruri V … +3 more , Bathula S, Park JS, Vemuganti R
Exp Neurol · 2026 Aug · PMID 41932563 · Publisher ↗
Chronic kidney disease (CKD) is an independent risk factor that worsens ischemic stroke outcomes. We characterized a gradient-progressive CKD mouse model using adenine injections (i.p.) that showed consistent CKD progres...
Chronic kidney disease (CKD) is an independent risk factor that worsens ischemic stroke outcomes. We characterized a gradient-progressive CKD mouse model using adenine injections (i.p.) that showed consistent CKD progression over 4 weeks and evaluated post-stroke outcomes for 2 weeks. Adenine (25-50 mg/Kg; i.p.) injected daily for up to 4 weeks promoted CKD in adult C57BL/6 mice. The progression of CKD in each mouse was tracked weekly using microbubble-assisted ultrasound and comprehensive blood chemistry. To determine if CKD progression has a direct impact on stroke outcomes, transient focal ischemia was induced after 2 and 4 weeks of CKD progression. Brain damage was assessed after 24 h of reperfusion by T2-MRI. To confirm whether the brain damage in CKD cohorts is due to cellular changes rather than flow dynamics, we evaluated cerebral blood flow using laser speckle and microSPECT, cerebral oxygen saturation, cardiac function by ultrasound, and bone density by DEXA scan. To determine the long-term effect of CKD on stroke outcomes, we evaluated motor function and survival up to 14 days of reperfusion. We assessed brain tissue from mice with only stroke and from CKD + stroke mice to identify proteomic changes using an apoptotic protein array. Our results showed that both the early and delayed phases of CKD induced severe brain damage and poor outcomes, and these changes were not due to alterations in flow dynamics but to direct effects on the brain vasculature. In addition, blood levels of kidney dysfunction and coagulant status markers were altered after stroke. We conclude that this is the first study to utilize CKD progression in a mouse model, evaluate synergistic outcomes, and test post-stroke outcomes at different severities of CKD.
Nrf2 modulates the IRF7-SLC31A1 axis to suppress neuronal cuproptosis after traumatic brain injury.
Feng S, Sun B, Tian L … +2 more , Li M, Sun G
Exp Neurol · 2026 Jul · PMID 41903734 · Publisher ↗
Traumatic brain injury (TBI) is one of the most prevalent neurological disorders and a major cause of death and disability worldwide. Cuproptosis is a recently identified form of cell death. Nuclear factor erythroid 2-re...
Traumatic brain injury (TBI) is one of the most prevalent neurological disorders and a major cause of death and disability worldwide. Cuproptosis is a recently identified form of cell death. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that has been widely investigated in TBI, may contribute to the regulation of cuproptosis. In this study, we investigated the role of cuproptosis in TBI and the regulatory mechanisms of Nrf2. We found that cuproptosis was induced following TBI in both patients and mouse models. In TBI mice, cuproptosis peaked at 3 days post-injury and predominantly occurred in neurons. Nrf2 deficiency aggravates neuronal cuproptosis after TBI, primarily through IRF7-mediated upregulation of SLC31A1. The Nrf2 activator dimethyl fumarate (DMF) suppresses neuronal injury and improves neurological function in TBI mice by inhibiting cuproptosis. Our results establish that cuproptosis is an important mechanism in TBI and that activation of Nrf2 mitigates TBI-induced cuproptosis by regulating the IRF7-SLC31A1 axis.
Does ACE2 deficiency have a role in Parkinson's disease -exacerbated pulmonary fibrosis?
Liu T, Zhang M, Wei J
Exp Neurol · 2026 Jul · PMID 41903733 · Publisher ↗
Pulmonary fibrosis is a common and life-threatening complication of Parkinson's disease (PD), yet the molecular mechanisms linking the two diseases remain unclear, creating a critical gap in targeted therapeutic strategi...
Pulmonary fibrosis is a common and life-threatening complication of Parkinson's disease (PD), yet the molecular mechanisms linking the two diseases remain unclear, creating a critical gap in targeted therapeutic strategies for comorbid patients. Angiotensin-converting enzyme 2 (ACE2) plays a key role in neuroprotection and lung homeostasis; its deficiency exacerbates PD-related neuroinflammation and α-synuclein aggregation, while also promoting pulmonary inflammation and fibrotic remodeling. Clarifying how ACE2 deficiency drives PD-exacerbated pulmonary fibrosis is therefore an urgent unmet need. This study explored the underlying mechanisms using MPTP-induced PD mouse models and bioinformatics analyses of PD/idiopathic pulmonary fibrosis (IPF) datasets from the GEO database. In MPTP-induced PD mice, ACE2 deficiency significantly worsened motor/non-motor dysfunction, dopaminergic neuron loss, microglial/astrocytic activation, and lung fibrosis (evidenced by elevated α-SMA/TGF-β and increased collagen deposition). Bioinformatics identified 41 overlapping differentially expressed genes (DEGs) between PD and IPF, enriched in critical pathways: downregulated FoxO1 (impairing antioxidant defense) and upregulated TNF, JAK1-STAT3, and AGE-RAGE (amplifying inflammation/fibrosis). ROC analysis validated hub genes (e.g., BDNF, FOSL2) with good diagnostic value (AUC > 0.7), and molecular docking identified Smilagenin, Fostamatinib, Olopatadine, and Amlexanox as potential therapeutics. This study confirms ACE2 deficiency is a central driver of PD-exacerbated pulmonary fibrosis via the FoxO1/TNF/JAK1-STAT3/AGE-RAGE pathways, providing novel biomarkers and drug candidates to address the clinical need for managing this comorbidity.
Glibenclamide alleviates hydrocephalus after intraventricular hemorrhage by targeting metabolic reprogramming of border-associated macrophages.
Guo P, Zhou J, Shi L … +7 more , Xiong B, Fan R, Li W, Chen Z, Chen Y, Yu A, Gong L
Exp Neurol · 2026 Jul · PMID 41895395 · Publisher ↗
BACKGROUND: Post-hemorrhagic hydrocephalus (PHH) following intraventricular hemorrhage (IVH) is a devastating complication associated with poor prognosis, primarily characterized by cerebrospinal fluid (CSF) absorption i...
BACKGROUND: Post-hemorrhagic hydrocephalus (PHH) following intraventricular hemorrhage (IVH) is a devastating complication associated with poor prognosis, primarily characterized by cerebrospinal fluid (CSF) absorption impairment due to meningeal fibrosis. Currently, effective pharmacological interventions targeting this fibrotic process are lacking. METHODS: In this study, utilizing a mouse model of IVH and a combination of immunofluorescence, flow cytometry, transcriptomic sequencing, and metabolic assays, we investigated the crosstalk between border-associated macrophages (BAMs) and meningeal fibroblasts during fibrosis. RESULTS: Our results demonstrated that IVH induces extensive activation of meningeal fibroblasts and pathological deposition of extracellular matrix (ECM). Specific depletion of BAMs significantly attenuated meningeal fibrosis, identifying them as critical drivers of this pathology. Mechanistically, IVH triggered distinct metabolic reprogramming in CD206+ BAMs, characterized by enhanced glycolysis and accumulation of mitochondrial reactive oxygen species (ROS). This metabolic stress drove BAMs to secrete profibrotic TGF-beta1, which subsequently activated downstream fibroblasts via paracrine signaling. Notably, we found that glibenclamide effectively targeted and inhibited the metabolic abnormalities and ROS production in BAMs, blocking TGF-beta1 release and consequently suppressing fibroblast activation, thereby ameliorating hydrocephalus. CONCLUSIONS: Collectively, our findings uncover the "BAM metabolic reprogramming-fibroblast activation" axis as a key pathophysiological driver of meningeal fibrosis and establish a novel mechanism for glibenclamide in preventing PHH through immunometabolic modulation, offering a promising therapeutic target for clinical intervention.
Senolytic therapy ameliorates high-fat diet-induced hippocampal senescence and cognitive decline in mice.
Xia X, Yi F, Zhang R … +11 more , Wu R, Zhang X, Zhang Y, Liu J, Qin H, He B, Duan Y, Xu Y, Huang XF, Yu Y, Hu M
Exp Neurol · 2026 Jul · PMID 41895394 · Publisher ↗
Obesity is a recognized risk factor for cognitive decline and neurodegenerative diseases, including Alzheimer's disease (AD). Obese individuals typically consume high-fat diet (HFD), particularly those rich in palmitate....
Obesity is a recognized risk factor for cognitive decline and neurodegenerative diseases, including Alzheimer's disease (AD). Obese individuals typically consume high-fat diet (HFD), particularly those rich in palmitate. However, the potential for HFD to induce neurodegeneration and their underlying mechanisms remain poorly understood. In this study, we demonstrate that HFD exposure induced significant deficits in hippocampal-dependent behaviors in mice and decreased synaptic protein expression. Transcriptomic analysis revealed differentially expressed genes in the hippocampus of HFD-fed mice, with enrichment predominantly in senescence-associated pathways. Furthermore, HFD-fed mice exhibited elevated hippocampal senescence markers, including increased SA-β-gal-positive cells, upregulated p16/p21 expression, elevated SASP factors and reduced Lamin B1. Remarkably, a palmitate-enriched diet recapitulated the hippocampal senescence phenotype and cognitive deficits induced by HFD, indicating that palmitate-the principal saturated fatty acid in HFD-served as a key mediator of cellular senescence. Finally, treatment with the senolytic cocktail dasatinib plus quercetin significantly reduced senescent cell burden, suppressed p16 protein expression, and normalized SASP factor levels. This intervention effectively restored cognitive function and synaptic protein expression. This work uncovers a novel HFD-induced cognitive impairment mechanism and suggests potential therapeutic strategies for mitigating obesity-associated neurodegeneration.
CIMT combined with BoNT-A regenerates skeletal muscle and improves upper limb function through activating IGF-1/FGFR2 axis in hemiplegic cerebral palsy.
Wang Y, Wu Q, Zhao X … +16 more , Luo J, Liang Y, Cai K, Wu L, Guo X, Zhong M, Zhang Y, Yang X, Peng T, Liu S, Li J, Liu L, He L, Liu X, Xu K, Tang H
Exp Neurol · 2026 Jul · PMID 41895393 · Publisher ↗
BACKGROUND: Hemiplegic cerebral palsy (HCP) is a prevalent cause of pediatric motor disability. Constraint-induced movement therapy (CIMT), when combined with botulinum neurotoxin type A (BoNT-A), improves upper limb fun...
BACKGROUND: Hemiplegic cerebral palsy (HCP) is a prevalent cause of pediatric motor disability. Constraint-induced movement therapy (CIMT), when combined with botulinum neurotoxin type A (BoNT-A), improves upper limb function and social participation in individuals with HCP. However, the mechanisms underlying the combined interventions remain unclear. METHODS: In this study, sixty children with CP were initially recruited and assigned to receive either CIMT or CIMT combined with BoNT-A intervention. The differences between the two therapeutic regimens were subsequently assessed using the Melbourne Assessment 2 (MA2) and the Modified Ashworth Scale (MAS). Subsequently, forty-six additional children with CP were enrolled. Fifteen children received CIMT and other thirty-one received CIMT combined with BoNT-A intervention. The serum samples were collected from these patients for proteomic analysis. Proteomic analysis was conducted to identify potential therapeutic targets of the CIMT and BoNT-A combined intervention in the serum of children with CP. HCP rats were treated with CIMT alone, the CIMT and BoNT-A combined intervention, or the combined intervention with the insulin-like growth factor-1 receptor (IGF-1R) inhibitor PQ401, respectively. ELISA was utilized to quantify IGF-1 levels in serum and skeletal muscle. Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were employed to observe muscle morphology. The expression of muscle satellite cells (MSCs) quiescence marker PAX7, early activation marker MyoD, and late activation marker MyoG were detected by fluorescent in situ hybridization and immunofluorescence double staining (FISH-IF). RNA sequencing (RNA-seq) was performed to identify down- stream targets of IGF-1. The expression of Fibroblast Growth Factor Receptor 2 (Fgfr2) was validated by quantitative real-time PCR (qRT-PCR). RESULTS: The combined intervention group exhibited significantly greater improvements in the MA2 and MAS test. Serum IGF-1 levels were significantly increased following the CIMT combined with BoNT-A intervention in children with CP. The combined intervention significantly improved forelimb function in rats, which was positively correlated with elevated IGF-1 levels in serum and skeletal muscle. Muscle fibers exhibited a more orderly arrangement, and the expression of PAX7, MyoD, and MyoG was higher in the combined intervention group than in the HCP group. In contrast, when treated with PQ401, a decline in forelimb function and a reversal of the therapeutic effects of CIMT combined with BoNT-A intervention was observed in HCP rats. RNA-seq identified Fgfr2 as a downstream target of IGF-1, and the combined intervention significantly upregulated Fgfr2 mRNA expression in the skeletal muscle of HCP rats. In contrast, the expression of Fgfr2 was downregulated when the combination intervention was administered alongside PQ401. CONCLUSION: CIMT combined with BoNT-A may enhance MSCs differentiation into skeletal muscle in HCP by upregulating the IGF-1/Fgfr2 pathway, providing new evidence for the mechanism of improving HCP by the combination intervention.
Freely moving pupillometry and awake vestibular recordings capture acute vestibular-autonomic signatures of motion sickness in mice.
Fang S, Wang B, Zhang SL … +7 more , Wu H, Yang ZJ, Guo WW, Jiang XX, Ren LL, Wang Y, Yang SM
Exp Neurol · 2026 Jul · PMID 41895392 · Publisher ↗
Motion sickness (MS) in rodents is commonly inferred from behavioral and autonomic readouts, but objective measures capturing ocular and vestibular involvement remain limited. Here we implemented a multimodal framework c...
Motion sickness (MS) in rodents is commonly inferred from behavioral and autonomic readouts, but objective measures capturing ocular and vestibular involvement remain limited. Here we implemented a multimodal framework combining freely moving pupillometry, awake vestibulo-ocular reflex (VOR), awake ocular vestibular evoked myogenic potentials (oVEMPs), and behavioral assays to characterize MS-like responses in mice. We further applied vestibular habituation training (VHT) to test whether these endpoints track adaptive recovery. Rotational stimulation induced a reproducible MS-like phenotype, including locomotor suppression, reduced feeding, and rapid hypothermia. Pupils dilated and ocular motility metrics decreased, yielding a reproducible ocular signature during vestibular conflict. Mydriasis coincided with robust c-Fos induction in the locus coeruleus (LC). Horizontal VOR gain decreased at low-mid stimulus frequencies, and oVEMPs showed reduced amplitude with prolonged latency, indicating dissociable vestibular readouts following rotation. After 14 days of VHT, behavioral, ocular, and vestibular measures largely returned toward control levels, consistent with adaptive recalibration. Together, this framework provides physiologically grounded endpoints beyond classical behavioral assays and may facilitate more precise characterization of vestibular conflict and its adaptive resolution in preclinical studies.
Novel Neurotrophin-3 peptidomimetic synthetic neurotrophin promotes neurological recovery after spinal cord injury.
Sefiani A, Horvat D, Pewklang T … +7 more , Thompson T, Morey S, Abdelfattah A, Samaie O, Hoar J, Burgess K, Geoffroy CG
Exp Neurol · 2026 Jul · PMID 41895391 · Publisher ↗
With 500,000 people paralyzed by traumatic spinal cord injuries (SCI) each year worldwide, there is a strong need for treatments that improve mobility and overall life quality after such injuries. There are currently no...
With 500,000 people paralyzed by traumatic spinal cord injuries (SCI) each year worldwide, there is a strong need for treatments that improve mobility and overall life quality after such injuries. There are currently no FDA-approved drugs that reliably improve locomotor function after injury. This is due to the complex nature of injury and our lack of ability to regenerate damaged areas of our central nervous system. Neurotrophin-3 (NT-3) is a neuroprotective, neuritogenic, pro-synaptogenic, and pro-myelinating neurotrophic factor. By binding to and activating the Tropomyosin receptor kinase (Trk) family of receptors, it supports regeneration and plasticity of neural circuits, improving cognitive and locomotor functions. NT-3 has a poor pharmacokinetic profile mitigating its clinical development, but mimicking NT-3 with small molecules with improved bioavailability is necessary for translational applications. Here, we determined 5c(i) (also known as NC101 and NRCR101), an NT-3 peptidomimetic synthetic neurotrophin, promotes neuron survival and neurite growth in adult cortical neurons. We demonstrated that 5c(i) promotes astrocytic wound healing in a scratch assay and induces pro-regenerative phenotypes in adult astrocytes. Using a severe preclinical SCI model, we demonstrate that delayed acute treatment with 5c(i) results in improved locomotor function and long-term memory without signs of adverse events, such as fatality or weight loss. Anatomical analysis of the spinal cords uncovered possible mechanisms for these neurological improvements; 5c(i) has pro-regenerative, pro-synaptogenic, pro-myelinating, and anti-inflammatory characteristics. Together, these data suggest 5c(i) has therapeutic potential to improve neurological outcome after SCI.
Disentangling causality in brain aging: The complex interplay between glial senescence, neuroinflammation, and neurodegeneration.
Suk K
Exp Neurol · 2026 Jul · PMID 41871753 · Publisher ↗
The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurodegeneration. While their co-occurrence is established, causal relationships remain poorly understo...
The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurodegeneration. While their co-occurrence is established, causal relationships remain poorly understood-a critical gap for developing mechanism-based therapies rather than symptomatic treatments. This review examines evidence for causality among glial senescence, neuroinflammation, and neurodegeneration using Bradford Hill criteria, longitudinal studies, genetic approaches, and senolytic trials. Glial senescence in astrocytes and microglia initiates neuroinflammatory cascades through the senescence-associated secretory phenotype (SASP), creating self-perpetuating cycles driving neuronal dysfunction. However, neuroinflammation also emerges as a primary event triggered by peripheral signals, blood-brain barrier breakdown, or pathogens, subsequently inducing glial senescence. Neuronal damage generates inflammatory signals activating glia, indicating bidirectional causality. Disease-specific patterns are heterogeneous: in Alzheimer's disease, early microglial activation may precede amyloid pathology, while in Parkinson's disease, gut-brain inflammation may initiate central pathology. Common feed-forward loops amplify initial insults-senescence, inflammation, or protein aggregation-transcending linear causality. We propose a framework recognizing critical temporal windows and tipping points, distinguishing reversible from irreversible stages. Anti-inflammatory and senolytic interventions show promise preventively or early but limited efficacy in advanced disease, emphasizing intervention timing. Outstanding questions include identifying earliest causal events, determining points of no return, and understanding genetic-environmental modification of causal pathways. Addressing these requires longitudinal multi-omics studies and interventional trials. Establishing causation beyond correlation enables precision medicine targeting root causes, offering hope for preventing age-related cognitive decline and neurodegeneration.
From mechanisms to clinical applications: Advances in 40 Hz gamma oscillation modulation for the treatment of neurological disorders.
Cai Y, Kang J, Xie H … +1 more , Wu D
Exp Neurol · 2026 Jul · PMID 41865782 · Publisher ↗
This review systematically summarizes the mechanisms of 40 Hz gamma rhythm neuromodulation and its research advances in neurological disorders. As a key rhythm for brain information integration, 40 Hz gamma oscillations...
This review systematically summarizes the mechanisms of 40 Hz gamma rhythm neuromodulation and its research advances in neurological disorders. As a key rhythm for brain information integration, 40 Hz gamma oscillations are generated by the interaction between excitatory and inhibitory neurons, and play a central role in cognitive functions such as attention and memory. They are commonly characterized by decreased power or loss of synchrony in various diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia, serving as a shared electrophysiological hallmark. Extrinsic 40 Hz stimulation (e.g., transcranial alternating current stimulation, light flickering, acoustic stimulation) can restore endogenous gamma rhythms through the entrainment effect, improve excitation-inhibition balance, enhance synaptic plasticity, and promote the clearance of pathological proteins by activating microglia and other mechanisms. Clinical studies have shown that this technology improves cognitive, emotional, and motor functions, with advantages of non-invasiveness and high safety. Despite challenges such as individual variability, marked methodological heterogeneity (e.g., inconsistent stimulation parameters, small sample sizes, and lack of multicenter randomized controlled trials), and unclear long-term effects, 40 Hz neuromodulation still demonstrates broad therapeutic potential and provides a novel rhythmic intervention strategy for neurological disorders.
Ddx20, DEAD-box helicase 20 is essential for maintaining microglial homeostasis.
Kawai Y, Bizen N, Nishiyama K … +1 more , Takebayashi H
Exp Neurol · 2026 Jul · PMID 41864319 · Publisher ↗
The properties of central nervous system microglia adjust dynamically in response to various environmental signals, under both normal and disease conditions. However, the regulation of microglia homeostasis is not well u...
The properties of central nervous system microglia adjust dynamically in response to various environmental signals, under both normal and disease conditions. However, the regulation of microglia homeostasis is not well understood. We hypothesize that the DEAD-box RNA helicase Ddx20 plays a key role in maintaining microglial homeostasis. To test this hypothesis, we generated mice with conditional deletion of Ddx20 in microglia using Iba1-iCre knock-in mice, and analyzed the effects of spinal cord injury and aging. Ddx20 ablation led to a drastic alteration of microglial morphology and a marked downregulation of gene networks involved in maintaining microglial identity, immune surveillance, and homeostatic functions; these effects become more prominent with spinal cord injury and aging. Our findings provide novel insights into the role of Ddx20 as a molecular regulator of microglial homeostasis and response to central nervous system injury.
Hippocampal astrocyte St6galnac5 silencing improves spatial memory and preserves synaptic integrity in an AD mouse model.
Xue C, Chen C, Zou X … +3 more , Li S, Lv Y, Liu W
Exp Neurol · 2026 Jul · PMID 41862120 · Publisher ↗
Cognitive resilience in Alzheimer's disease (AD) requires the maintenance of synaptic integrity despite progressive pathological insults. Reactive astrocytes can switch between neuroprotective and neurotoxic states, and...
Cognitive resilience in Alzheimer's disease (AD) requires the maintenance of synaptic integrity despite progressive pathological insults. Reactive astrocytes can switch between neuroprotective and neurotoxic states, and their maladaptive transition significantly accelerates neurodegeneration, yet the molecular drivers of this shift remain elusive. Here, using published single-nucleus transcriptomic data, we identified the sialyltransferase St6galnac5 as a candidate regulator associated with reactive, pro-inflammatory astrocyte states. We further show that astrocyte-specific, AAV-mediated knockdown of St6galnac5 in female 3xTg-AD mice improves spatial learning, memory and anxiety-like behaviors. Neuropathological assessment revealed that this functional recovery was underpinned by a marked reduction in amyloid-β and tau pathologies, alongside the preservation of synaptic integrity. Consistent with a shift toward a less inflammatory astrocyte state, St6galnac5 knockdown decreased A1-associated markers and increased A2-associated markers in vitro and alleviated neurite outgrowth deficits in neuron-astrocyte co-culture. Together, our findings identify St6galnac5 as a critical molecular switch driving astrocytic dysfunction in AD, and further propose that targeted inhibition of this sialylation pathway represents a viable strategy to bolster astrocytic resilience and slow disease progression.
Investigating the behavioral impact of tropical almond (Terminalia catappa L.) consumption: Anxiolytic effects and memory preservation in aged rats.
de Oliveira ND, Viera VB, Dantas BS … +5 more , Dutra LMG, Oliveira ACS, Silva GS, de Freitas JCR, Soares JKB
Exp Neurol · 2026 Jul · PMID 41862119 · Publisher ↗
Terminalia catappa L. (TC) has been traditionally used for its medicinal properties, including antioxidant and neuroprotective effects. Considering the increased vulnerability to cognitive decline and anxiety in aging, w...
Terminalia catappa L. (TC) has been traditionally used for its medicinal properties, including antioxidant and neuroprotective effects. Considering the increased vulnerability to cognitive decline and anxiety in aging, we investigated the potential impact of TC on anxiety-like behavior, memory, and oxidative stress in aged Wistar rats. Male Wistar rats were used, including young adults (70 days old) and aged animals (17 months old). The aged rats were allocated into three groups: control (n = 11), TC500 (n = 12), and TC1000 (n = 12). TC was administered by oral gavage at doses of 500 mg/kg or 1000 mg/kg for five weeks. Behavioral tests were conducted to assess anxiety: Open field, elevated plus maze, and light-dark box, and memory performance: Object recognition test and water maze, and oxidative stress markers were analyzed in brain tissue. TC-treated animals showed increased ambulation, rearing, grooming, time spent in open arms and central areas of the elevated plus maze, and increased head-dipping behavior, indicating anxiolytic-like effects. These findings were reinforced by greater time spent in the light compartment and higher transition rates in the light-dark box test, as well as increased exploration of novel objects in short- and long-term memory tasks. In the Morris water maze, the TC groups exhibited improved memory, demonstrated by shorter escape latency and greater total distance traveled. Both treatment groups showed reduced lipid peroxidation levels in brain tissue, suggesting decreased oxidative stress. These results indicate that TC may exert anxiolytic-like effects, enhance memory performance, and reduce oxidative stress in aged rats, supporting its potential as a neuroprotective agent in aging-related conditions.
TREM2 as a possible link between Alzheimer's disease and diabetes mellitus.
Chen W, Huang N, Huang W … +3 more , Wang M, Luo Y, Huang J
Exp Neurol · 2026 Jul · PMID 41862118 · Publisher ↗
Alzheimer's disease (AD) and diabetes mellitus (DM) represent escalating global health burdens, with epidemiological and clinical studies demonstrating a strong association between them. Diabetic patients face a signific...
Alzheimer's disease (AD) and diabetes mellitus (DM) represent escalating global health burdens, with epidemiological and clinical studies demonstrating a strong association between them. Diabetic patients face a significantly increased risk of AD, and poor glycemic control can accelerate AD progression. Chronic low-grade inflammation is increasingly recognized as a central mechanism bridging the two diseases. Triggering receptor expressed on myeloid cells 2 (TREM2), a key immune regulator, has emerged as a critical player in both AD and DM. In AD, TREM2 is specifically expressed on microglia, mediating neuroinflammatory and neurodegenerative processes while regulating both amyloid-β (Aβ) and Tau pathology. In DM, TREM2 contributes to insulin resistance and metabolic dysregulation. Genetic variants of TREM2 are established risk factors for AD, while altered TREM2 expression correlates with DM pathology. This review summarizes TREM2's structural and functional characteristics, its dual roles in AD and DM, and its potential as a therapeutic target. Elucidating these shared TREM2-mediated mechanisms may provide novel insights into the pathological interplay between AD and DM and inform precision therapeutic strategies.
Neuroprotective effect of RMF in a mouse model of sporadic Parkinson's disease.
Anayyat U, Mei X, Zhang F … +7 more , Yi R, Yang X, Yang Z, Li K, Zheng G, Wei Y, Wang X
Exp Neurol · 2026 Jul · PMID 41862117 · Publisher ↗
The progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) due to the aggregation of Lewy bodies is the hallmark of Parkinson's disease (PD). ROS play a key role in the formation of Lewy bo...
The progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) due to the aggregation of Lewy bodies is the hallmark of Parkinson's disease (PD). ROS play a key role in the formation of Lewy bodies, thus leading to mitochondrial dysfunction and the apoptosis of neurons. A rotating magnetic field (RMF) is an emerging noninvasive technique for the prevention of neurodegenerative disorders. To investigate the potential therapeutic effects of RMS in PD, we subjected an experimental mouse model to RMF. CblC mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg, i.p., once daily for 5 days), followed by RMF treatment at a frequency and intensity of 4 Hz and 0.4 T, respectively. The daily 2-h RMF treatment was continued for a period of 6 months. We examined the effects of RMF on motor functions, the aggregation of Lewy bodies and the integrity and viability of total and dopaminergic neurons in the SNpc and striatal regions. We further performed transcriptomic analysis of SNpc tissue from PD and SHAM mice. Our results showed that exposure to RMF improved motor functions, enhanced neuronal cell viability and protected neuronal integrity in a PD mouse model. We further showed that RMF diminishes the number of aggregated Lewy bodies in neurons and reduces ROS production. Overall, the results of the transcriptomic analysis revealed that RMF promoted the expression of anti-apoptotic genes rather than proapoptotic genes that are specifically involved in mitochondrial apoptosis.
A review on cellular ferroptosis in traumatic brain injury: Mechanisms and therapeutic implications.
Qiang JL, Ren MM, Yuan YS … +5 more , Yang XG, Quan XP, Zhu RT, Zhang M, Zhu J
Exp Neurol · 2026 Jul · PMID 41856450 · Publisher ↗
Traumatic brain injury (TBI) remains a major cause of mortality and long-term neurological disability worldwide, with secondary brain injury playing a critical role in disease progression. Increasing evidence indicates t...
Traumatic brain injury (TBI) remains a major cause of mortality and long-term neurological disability worldwide, with secondary brain injury playing a critical role in disease progression. Increasing evidence indicates that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is a key contributor to secondary neuronal damage after TBI. This review systematically summarizes the core mechanisms of ferroptosis in TBI, focusing on blood-brain barrier (BBB) disruption-associated iron dysregulation, polyunsaturated fatty acids (PUFAs)-driven lipid peroxidation, and dysfunction of the glutathione-glutathione peroxidase 4 (GSH-GPX4) axis. We further highlight the extensive crosstalk between ferroptosis and other regulated cell death pathways, including apoptosis, necroptosis, and pyroptosis, mediated by shared upstream triggers and key molecular nodes. Ferroptosis is discussed in a stage-dependent manner across the acute, subacute, and chronic phases of TBI. Emerging ferroptosis-targeted therapeutic strategies, including ferroptosis inhibitors, traditional Chinese medicine (TCM)-derived compounds, gene therapy, and nanomaterial-based delivery systems, are critically reviewed. Finally, current translational challenges and future perspectives for ferroptosis-targeted precision therapy in TBI are discussed.
Rapamycin treatment reduces CD11c microglia and increases amyloid plaque load in 5xFAD mice.
Ouk K, Fernández-Klett F, Schormann E … +6 more , Greiner A, Santaella A, Fernández-Zapata C, Böttcher C, Krüger E, Priller J
Exp Neurol · 2026 Jul · PMID 41855773 · Publisher ↗
The mammalian target of rapamycin (mTOR) is involved in immune regulation and in the metabolism of β-amyloid (Aβ) and tau peptides in Alzheimer's disease (AD). In this study, we investigated the effects of the mTOR inhib...
The mammalian target of rapamycin (mTOR) is involved in immune regulation and in the metabolism of β-amyloid (Aβ) and tau peptides in Alzheimer's disease (AD). In this study, we investigated the effects of the mTOR inhibitor, rapamycin, on central and peripheral immune profiles, proteasome activity, Aβ pathology, and spontaneous exploratory activity and place recognition in the 5xFAD mouse model of amyloid pathology. Using flow cytometry, we found that rapamycin induced changes in immune cell numbers and phenotypes in 5xFAD mice, notably a significant decrease of CD11c microglia in cortex and hippocampus of 5xFAD mice. This was associated with increased Aβ plaque load. Concomitantly, we observed a decrease in immunoproteasome content and activity. In peripheral blood, rapamycin treatment resulted in higher percentages of granulocytes, whereas splenic T lymphocytes were reduced. No changes in the open field and modified Y-maze tests were observed following rapamycin treatment in wild-type and 5xFAD mice. Our results reveal detrimental effects of rapamycin on amyloid plaque accumulation and CD11c disease-associated microglial subsets in cortex and hippocampus of 5xFAD mice, which is an important finding given two ongoing phase 2 clinical studies of rapamycin treatment in AD.
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