Exp. Neurol. [JOURNAL]
Sun
200 papers
Kallikrein-8 contributes to kallikrein-kinin system dysregulation in Alzheimer's disease.
Raza SA, Pereira de Almeida P, Farid I … +6 more , Macha N, Knoll M, Roser P, Scherbaum N, Herring A, Keyvani K
Exp Neurol · 2026 Sep · PMID 42140379 · Publisher ↗
Neuroinflammation is a central feature of Alzheimer's disease (AD), yet the mechanisms linking inflammatory protease systems to disease pathology remain incompletely understood. The kallikrein-kinin system (KKS), a major...
Neuroinflammation is a central feature of Alzheimer's disease (AD), yet the mechanisms linking inflammatory protease systems to disease pathology remain incompletely understood. The kallikrein-kinin system (KKS), a major source of bradykinin, has been associated with AD mainly at the peripheral level, but its regulation within the human brain remains largely unexplored. Here, we investigated KKS activity in human AD tissue and a transgenic mouse model, with a particular focus on serine protease kallikrein-8 (KLK8). We observed that both bradykinin and bradykinin B1 receptor levels are increased in the hippocampus of AD patients, with a pronounced upregulation in females. In the TgCRND8 mouse model of AD, hippocampal bradykinin levels were also elevated, while heterozygous KLK8 knockout ameliorated this pathological effect, supporting a functional contribution of KLK8. Analysis of kallikrein expression revealed a selective increase in KLK8 in the AD hippocampus, whereas the canonical kinin-generating proteases, tissue kallikrein (KLK1) and plasma kallikrein (KLKB1), remained unchanged. In vitro cleavage assays demonstrated that recombinant human KLK8 can process both low- and high-molecular-weight kininogens, and functional assays confirmed that KLK8 increases bradykinin levels in human hippocampal tissue and plasma, an effect that was blocked by a KLK8-neutralizing antibody. Together, these findings identify KLK8 as a previously unrecognized modulator of the KKS in the AD brain. Our data support a model in which elevated KLK8 contributes to dysregulated bradykinin production and B1R signaling, providing a mechanistic link between KLK8 activity and neuroinflammation in Alzheimer's disease.
The Glymphatic system: A dynamic regulator of brain health and therapeutic target.
Wang X, Gao M, Sui S … +9 more , Liu F, Tian W, Wu S, Ding J, Chao X, Xie X, Gu M, Hu T, Sun W
Exp Neurol · 2026 Sep · PMID 42134763 · Publisher ↗
The central nervous system (CNS) maintains homeostasis despite high metabolic activity and the apparent absence of conventional lymphatic vessels within the parenchyma. The identification of the glymphatic system-a glial...
The central nervous system (CNS) maintains homeostasis despite high metabolic activity and the apparent absence of conventional lymphatic vessels within the parenchyma. The identification of the glymphatic system-a glial-dependent perivascular network-proposes a mechanistic framework for interstitial waste clearance. This review presents a systems-level framework that views the glymphatic network as a dynamic regulator of brain homeostasis, essential for neurophysiological stability. We examine the biophysical determinants of solute transport, emphasizing the critical role of polarized aquaporin-4 (AQP4) channels and navigating the ongoing scientific debate regarding the relative contributions of convective bulk flow versus diffusion. We further analyze central regulation of clearance efficiency by the sleep-wake cycle, circadian rhythms, and state-dependent interstitial ionic fluctuations. Pathologically, we consider glymphatic dysfunction as a convergent mechanism across diverse disorders, potentially contributing to proteostasis failure in neurodegeneration, exacerbating secondary injury after stroke and trauma, linking systemic metabolic conditions to CNS impairment, and presenting emerging evidence for its role in major psychiatric disorders, including depression, bipolar disorder, and schizophrenia. Finally, we evaluate strategies to restore clearance capacity through lifestyle and pharmacological interventions; the translational potential of leveraging perivascular pathways for CNS drug delivery; and the need for developing non-invasive imaging biomarkers to enable preventative neurology. Unlike previous reviews that have largely summarized the system's anatomy and physiology, we integrate three underappreciated dimensions: (i) state-dependent neurobiological control by sleep and circadian timing; (ii) glymphatic failure as a shared systems-level mechanism across acute and chronic neurological and psychiatric disorders; and (iii) the dual translational relevance of the perivascular pathway as both a therapeutic target and a drug-delivery route.
Therapeutic properties of ayahuasca component N,N-Dimethyltryptamine in a pre-clinical model of Parkinson's disease.
Calleja-Conde J, Echeverry-Alzate V, Sanz-SanCristobal M … +6 more , Alonso-Gil S, Giné E, Bühler K, López-Moreno JA, Perez-Castillo A, Morales-García JA
Exp Neurol · 2026 Sep · PMID 42128256 · Publisher ↗
Parkinson's disease is a progressive neurodegenerative disorder with increasing global prevalence, primarily driven by population ageing. A hallmark of the disease is the degeneration of nigrostriatal dopaminergic neuron...
Parkinson's disease is a progressive neurodegenerative disorder with increasing global prevalence, primarily driven by population ageing. A hallmark of the disease is the degeneration of nigrostriatal dopaminergic neurons, accompanied by marked activation of glial cells and a sustained neuroinflammatory response. Current pharmacological treatments are limited to symptomatic relief and do not halt or reverse disease progression. Ayahuasca, a traditional Amazonian psychoactive brew, has attracted growing scientific interest for its potential therapeutic effects in neuropsychiatric and neurodegenerative conditions. Its principal psychoactive compound, N,N-dimethyltryptamine (DMT), acts as an agonist at the 5-HT2A serotonin receptor-responsible for its hallucinogenic properties-and at the sigma-1 receptor, a molecular target implicated in neuroprotection and modulation of inflammation. This study investigates the neuroprotective and anti-inflammatory potential of DMT in a preclinical model of Parkinson's disease. Our findings demonstrate that DMT administration results in molecular changes within the nigrostriatal pathway consistent with reduced neuroinflammation and neuronal preservation. Furthermore, behavioral assessments indicate symptomatic improvements following treatment. These results support the therapeutic potential of DMT as a disease-modifying agent in Parkinson's disease and warrant further investigation.
Anti-inflammatory and anti-oxidative effects of vanadium on motor and cerebellar cortices of juvenile hydrocephalic mice.
Olopade FE, Femi-Akinlosotu OM, Ugwuorah JC … +3 more , Oyagbemi A, Olopade JO, Shokunbi MT
Exp Neurol · 2026 Sep · PMID 42128255 · Publisher ↗
Hydrocephalus presents a significant clinical neurology challenge, manifesting complications such as neuronal degeneration, cognitive impairments and motor deficits. Ventricular shunting is the primary recourse for treat...
Hydrocephalus presents a significant clinical neurology challenge, manifesting complications such as neuronal degeneration, cognitive impairments and motor deficits. Ventricular shunting is the primary recourse for treatment, but it is fraught with complications such as infection and obstruction. Due to the need for alternative therapeutic modalities, vanadium, a ubiquitous transition metal known for its promising therapeutic potential in neurological conditions, has recently been studied. This study investigates the anti-inflammatory and anti-oxidative effects of vanadium on the motor and cerebellar cortices in juvenile hydrocephalic mice following treatment with two doses of vanadium. Forty juvenile mice were divided into four cohorts (n = 10 each): control, hydrocephalus-only, low (0.3 mg/kg) and high (3 mg/kg) dose vanadium groups. Hydrocephalus was induced by intracisternal injection of kaolin, and sodium metavanadate was administered daily by intraperitoneal injection for 14 days. Neurobehavioral assessments: Inverted square grid test and pole test were conducted to evaluate muscular strength, motor coordination/balance, learning and memory, respectively. The cerebral motor and cerebellar cortices underwent cresyl violet staining and immunohistochemistry targeting inflammatory markers- Aquaporin-4 (AQP4), Tumor Necrosis Factor-α (TNF-α) and the astrocytic marker -Glial Fibrillary Acidic Protein (GFAP). Additionally, biochemical assays measuring TNF-α, Interleukin 1-β (IL-1β), Superoxide Dismutase (SOD), and Glutathione-S-Transferase (GST) activities were performed. Hydrocephalic mice exhibited significant weight loss and pronounced neurobehavioral deficits, characterized by diminished motor function and impaired cognitive function. Histological staining, AQP4, GFAP and TNF-α immunostaining revealed pyknotic cells, reactive astrocytes, and increased AQP4 and TNF-α expression. Biochemical analyses revealed increased TNF-α and IL-1β levels, accompanied by reduced SOD and GST activities in hydrocephalus-only group. These were all ameliorated in both vanadium-treated groups. In conclusion, this study highlights promising anti-inflammatory and anti-oxidative effects of vanadium treatment in mitigating neuroinflammation and oxidative stress associated with hydrocephalus.
Progress in animal models of rapid eye movement sleep behavior disorder: Characteristics and applications.
Wang S, Cui Y, Zhang M … +5 more , Zhao W, Wang L, Han B, Zheng H, Tuo H
Exp Neurol · 2026 Sep · PMID 42128254 · Publisher ↗
Rapid eye movement sleep behavior disorder (RBD) is characterized by the loss of muscle atonia during rapid eye movement (REM) sleep, leading to the enactment of vivid and often unpleasant dreams. Studies have shown that...
Rapid eye movement sleep behavior disorder (RBD) is characterized by the loss of muscle atonia during rapid eye movement (REM) sleep, leading to the enactment of vivid and often unpleasant dreams. Studies have shown that it is closely related to alpha-synuclein neurodegenerative diseases, particularly Parkinson's disease (PD) and dementia with Lewy bodies (DLB). RBD serves not merely as an early warning signal but also is a manifestation of the pathogenesis of PD. Therefore, elucidating the pathological mechanisms underlying RBD is essential for enhancing the accuracy of early diagnosis and developing effective treatments for PD and DLB. Animal models remain fundamental in this research, enabling the exploration of specific pathophysiological traits, behavioral phenotypes, and potential therapeutic interventions. This review synthesizes recent advances in RBD modeling, including methodologies for model construction, core pathological mechanisms, and associated behavioral phenotypes. By examining the limitations of existing paradigms and proposing new avenues for research, we aim to provide a deeper insight into the mechanistic link between RBD and parkinsonian pathology.
Neuro-osteo crosstalk: The sympathetic nervous system as a key driver of SCI-induced osteoporosis.
Bryan JA, Jackson W, Lemmens N … +1 more , Hook MA
Exp Neurol · 2026 Sep · PMID 42128253 · Publisher ↗
Bone loss is a significantly underestimated secondary consequence of spinal cord injury (SCI), affecting more than 80% of people living with SCI. While this form of bone loss has been traditionally attributed to disuse,...
Bone loss is a significantly underestimated secondary consequence of spinal cord injury (SCI), affecting more than 80% of people living with SCI. While this form of bone loss has been traditionally attributed to disuse, the severity, rapid onset and resistance to conventional therapies suggest that there are additional mechanisms involved. This review explores preclinical and clinical evidence implicating sympathetic dysfunction as a key contributor to SCI-induced osteoporosis. Increasing evidence positions the SNS a central regulator of bone homeostasis and hematopoiesis. We describe the anatomical and functional innervation of bone by sympathetic fibers and detail how norepinephrine can act through distinct adrenergic receptor subtypes to differentially regulate osteoblast activity, osteoclastogenesis, mesenchymal lineage commitment, and immune cell activity within the bone marrow microenvironment. We further examine how SCI disrupts these processes across the acute and chronic phases following injury through a catecholamine storm, decentralized sympathetic reflexes, chronic inflammation, and circadian desynchronization. Collectively, these changes can drive uncoupled bone remodeling and accelerate bone loss. Finally, we discuss therapeutic implications of targeting SNS signaling, including receptor subtype-selective strategies, combination therapies, neuro-osteo-immune modulation, and biomarker-driven early detection. By reframing SCI-induced osteoporosis as a consequence of autonomic dysregulation rather than disuse alone, this review calls attention to new mechanistic insight and highlights the SNS as a promising therapeutic target for prevention and intervention.
Advances in hibernation research: Implications for neurological disease and recovery.
Singhal NS, Ma DK
Exp Neurol · 2026 Sep · PMID 42119934 · Publisher ↗
Abstract loading — click title to view on PubMed.
Aspirin mitigates sepsis-associated encephalopathy by modulating ICAM-1 and MMP-9 signaling: Evidence from clinical cohorts and mechanistic experiments.
Cui Y, Lu S, Lv K … +7 more , Zhang H, Pang M, Wang H, Tian X, Chen H, Qiu J, Wang H
Exp Neurol · 2026 Sep · PMID 42119687 · Publisher ↗
Sepsis-associated encephalopathy (SAE) is a devastating complication contributing substantially to intensive care unit mortality and long-term cognitive impairment. Although observational studies suggest that aspirin use...
Sepsis-associated encephalopathy (SAE) is a devastating complication contributing substantially to intensive care unit mortality and long-term cognitive impairment. Although observational studies suggest that aspirin use was associated with reduced sepsis-related mortality, its neuroprotective potential against SAE and underlying molecular mechanisms remain unclear. Using data from the Medical Information Mart for Intensive Care IV and eICU Collaborative Research Database, we demonstrated through propensity score matching and inverse probability of treatment weighting that aspirin use was significantly associated with reduced SAE incidence without increased gastrointestinal bleeding risk. Meta-analysis yielded a pooled protective association (OR 0.69, 95% CI 0.57-0.83) with moderate heterogeneity (I = 63.6%). Transcriptomic profiling of hippocampal tissues from lipopolysaccharide (LPS)-induced SAE mice revealed intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) as aspirin-responsive hub genes enriched in leukocyte adhesion and extracellular matrix remodeling pathways. In murine models, aspirin significantly improved cognitive performance in novel object recognition and Y-maze tests, while reducing anxiety-like behavior. Mechanistically, aspirin suppressed LPS-induced upregulation of ICAM-1 and MMP-9 expression in hippocampus and prefrontal cortex, preserved blood-brain barrier integrity by restoring tight junction-related and adherens junction-related proteins reducing Evans blue extravasation, attenuated neuroinflammatory signaling through decreased cyclooxygenase-2, nuclear factor-κB, tumor necrosis factor-α, interleukin-6, and prostaglandin E2 expression, and reduced cleaved caspase-3-mediated neuronal apoptosis. These findings provide convergent evidence that aspirin mitigates SAE through suppression of ICAM-1 and MMP-9-associated inflammatory and endothelial dysfunction, supporting its potential as a neuroprotective adjunctive therapy and identifying ICAM-1 and MMP-9 as promising therapeutic targets for SAE.
Intraoperative cerebral blood flow threshold standardization in a mouse model of global cerebral ischemia: Parallel evaluation of laser doppler flowmetry and laser speckle contrast imaging.
Zhang Z, Zhou G, Wang S … +3 more , Guo H, Hou W, Cai Y
Exp Neurol · 2026 Sep · PMID 42114613 · Publisher ↗
OBJECTIVES: Bilateral common carotid artery occlusion (BCCAO) is a widely used mouse model of global cerebral ischemia (GCI). However, marked inter-animal variability in ischemic severity, largely driven by anatomical he...
OBJECTIVES: Bilateral common carotid artery occlusion (BCCAO) is a widely used mouse model of global cerebral ischemia (GCI). However, marked inter-animal variability in ischemic severity, largely driven by anatomical heterogeneity of posterior communicating arteries (PcomAs), limits the reproducibility and comparability of this model. Although intraoperative real-time cerebral blood flow (CBF) monitoring offers a potential functional tool for predicting ischemic severity, validated threshold criteria for different monitoring platforms remain lacking. METHODS: GCI was induced in male C57BL/6J mice by 20 min of BCCAO. Cortical CBF was continuously monitored intraoperatively using either Laser Doppler Flowmetry (LDF) or Laser Speckle Contrast Imaging (LSCI). ROC analysis and K-means clustering were used to define optimal CBF reduction thresholds. Ischemic injury was evaluated by Nissl staining, H&E staining, and TUNEL staining in the hippocampal CA1 region at multiple time points after reperfusion. Functional outcomes were assessed using the Y-maze and contextual fear conditioning tests. RESULTS: PcomA score was significantly associated with the magnitude of intraoperative CBF reduction. ROC analysis identified an LDF-measured CBF reduction of ≥85% as the optimal threshold for distinguishing mice with low-collateral phenotype, whereas the corresponding threshold for LSCI was ≥80%. Mice meeting these thresholds showed pronounced delayed neuronal loss and increased apoptosis in the hippocampal CA1 region, together with selective impairments in spatial working memory and contextual memory, while basal motor performance remained preserved. CONCLUSION: This study establishes platform-specific intraoperative CBF reduction thresholds for two commonly used monitoring modalities in the mouse BCCAO model (LDF ≥ 85%; LSCI ≥80%).
The emerging role of polo-like kinase 2 in Alzheimer's disease.
Martínez-Drudis L, Sheta R, Musiol D … +2 more , Teixeira M, Oueslati A
Exp Neurol · 2026 Sep · PMID 42107623 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau tangles. Protein phosphorylation is increasingly recognized as a key m...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau tangles. Protein phosphorylation is increasingly recognized as a key modulator of AD pathology, but the specific kinases involved remain incompletely characterized. Polo-like kinase 2 (PLK2), a serine/threonine kinase previously studied in Parkinson's disease, has recently emerged as a potential contributor to AD pathogenesis. This review explores the physiological and pathological roles of PLK2, emphasizing its expression in the brain, its regulation by neuronal activity, and its involvement in synaptic homeostasis. Evidence from postmortem brain studies, in vivo models, and cell-based experiments indicates that PLK2 is associated with AD through multiple mechanisms. PLK2 has been shown to modulate the amyloidogenic processing of amyloid precursor protein (APP), is associated with increased Aβ production, and can directly phosphorylates APP at critical sites. Elevated PLK2 levels have also been associated with reduced APP surface expression and increased endocytosis, changes that are consistent with enhanced Aβ generation. Although direct phosphorylation of Tau by PLK2 has not been clearly established, recent findings suggest that PLK2 activity can modulate Tau protein levels and influence its phosphorylation state, potentially through regulation of other kinases and phosphatases. Pharmacological inhibition of PLK2 has shown promising effects in transgenic mouse models of AD, including modulation of Aβ and Tau pathology and improvement in cognitive performance, with some sex-specific responses. While these findings support a contributory role for PLK2 in AD-relevant pathways, its precise position within the causal hierarchy of disease progression remains to be fully established.
Oligodendrocyte lineage cell-specific GPR17/Gelsolin signaling regulates remyelination and cognitive recovery after subarachnoid hemorrhage.
Tan S, Wang Y, Li X … +6 more , Zhu Y, Huang Z, Deng C, Tang R, Zhong J, Guo Z
Exp Neurol · 2026 Sep · PMID 42107622 · Publisher ↗
AIMS: Cognitive impairment following subarachnoid hemorrhage (SAH) is strongly associated with myelin sheath damage. G protein-coupled receptor 17 (GPR17) is a stage-specific regulator of oligodendrocyte lineage cell (OL...
AIMS: Cognitive impairment following subarachnoid hemorrhage (SAH) is strongly associated with myelin sheath damage. G protein-coupled receptor 17 (GPR17) is a stage-specific regulator of oligodendrocyte lineage cell (OLC) differentiation; however, its role in post-SAH remyelination and cognitive recovery remains incompletely understood. This study aimed to elucidate the function of GPR17 in OLCs after SAH and to identify its downstream effector mechanism. METHODS: A mouse model of SAH was established to assess cognitive function, myelin integrity, OLC differentiation, and GPR17 expression. Conditional knockout mice were generated to selectively delete GPR17 in early- or late-stage OLCs. Behavioral tests, histopathological analyses, and myelin-related evaluations were conducted after SAH. Transcriptomic sequencing was performed to identify downstream signaling pathways regulated by GPR17. RESULTS: SAH induced a 2.3-fold increase in GPR17+ OLCs at day 7, along with a 42% reduction in mature OLCs and a 41% decrease in MBP expression. Selective deletion of GPR17 in late-stage OLCs-but not in early-stage OLCs-significantly improved cognitive performance after SAH, which was associated with enhanced OLC differentiation and myelin repair. Transcriptomic analysis identified Gelsolin as a critical downstream mediator. Knockdown of Gelsolin abolished the promyelinating and cognitive benefits conferred by late-stage GPR17 deletion. CONCLUSION: Stage-specific inhibition of GPR17 in late-stage OLCs promotes remyelination and enhances cognitive recovery after SAH through a Gelsolin-dependent mechanism. The GPR17/Gelsolin signaling pathway represents a promising therapeutic target for post-SAH cognitive impairment.
Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.
Khattab NA, El Kadeem A, Goda AE … +2 more , El-Mahdy NA, El-Shitany N
Exp Neurol · 2026 Sep · PMID 42107621 · Publisher ↗
Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for dise...
Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.
Corrigendum to "Recombinant OX40 attenuates neuronal apoptosis through OX40-OX40L/PI3K/AKT signaling pathway following subarachnoid hemorrhage in rats" [Experimental Neurology, 326 (2020), 113179-113,190/ PMID:31930990].
Wu LY, Enkhjargal B, Xie ZY … +7 more , Travis ZD, Sun CM, Zhou KR, Zhang TY, Zhu QQ, Hang CH, Zhang JH
Exp Neurol · 2026 Aug · PMID 42106215 · Publisher ↗
Abstract loading — click title to view on PubMed.
Diaphragm hypertrophy and spinal stress response accompany phrenic myelin defects in a murine model of Charcot-Marie-Tooth Disease Type 1E.
Bazick H, Seipel R, Defilippi V … +5 more , Heredia DJ, Procacci NM, Gould TW, Falk DJ, Notterpek L
Exp Neurol · 2026 Sep · PMID 42105803 · Publisher ↗
Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, early-onset dysmyelinating neuropathy linked with point mutations in the peripheral myelin protein 22 (PMP22) gene. Respiratory problems are known to impact neuropat...
Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, early-onset dysmyelinating neuropathy linked with point mutations in the peripheral myelin protein 22 (PMP22) gene. Respiratory problems are known to impact neuropathic patients, yet existing studies have not characterized this pathophysiology in corresponding animal models. Trembler J (TrJ) mice carry the same Leu16Pro amino acid substitution in the PMP22 protein that is present in families diagnosed with CMT1E. Utilizing electrophysiological, biochemical and morphological approaches, we examined critical sites of the lower respiratory system, including the diaphragm, phrenic nerve and cervical (C3-C6) region of the spinal cord in adult age-matched wild type (Wt) and heterozygous TrJ mice. In response to high-frequency stimulation of the presynaptic phrenic nerve, diaphragm muscle fibers of neuropathic mice exhibited similar rundown in the release of acetylcholine, but failed to maintain action potentials, suggesting a postsynaptic, muscle-derived deficit in neurotransmission. Although muscle fiber subtype numbers were unaffected in neuropathic mice, cross-sectional areas were enlarged in all fiber subtypes. Additionally, the ubiquitin-proteasome and autophagy pathways were upregulated in muscle, suggesting compensatory remodeling that occurred concurrently with, or because of, impaired neurotransmission. Analyses of phrenic nerve sections revealed highly significant (p < 0.0001) myelin defects, axonal atrophy, and astrogliosis, accompanied by stress granule formation within the grey matter of the cervical spinal cord. These findings identify profound structural and functional deficits of the respiratory system in TrJ mice modeling CMT1E and establish phrenic neuropathy as a mechanism underlying neuronal stress responses in the cervical spinal cord as well as postsynaptic diaphragm dysfunction.
High-fat diet drives progressive neuroinflammation and neuronal apoptosis via microglial activation: TSPO PET reveals reversal of pathology after dietary switching.
Wang Y, Lin Y, Xue Q … +3 more , Lin K, Lin X, Miao W
Exp Neurol · 2026 Sep · PMID 42105802 · Publisher ↗
OBJECTIVE: Neuroinflammation has been identified as a risk factor for cognitive decline and depression, and obesity is closely associated with neuroinflammation. The purpose of this study was to clarify the effect of obe...
OBJECTIVE: Neuroinflammation has been identified as a risk factor for cognitive decline and depression, and obesity is closely associated with neuroinflammation. The purpose of this study was to clarify the effect of obesity induced by long-term high-fat diet on neuroinflammation in mice, verify the reliability of TSPO-targeted PET/CT as a non-invasive imaging biomarker for neuroinflammation, and evaluate the reversal effect of dietary intervention. METHODS: Two-month-old male C57BL/6 J mice were randomly divided into three groups: the normal chow diet group (NCD), the high-fat diet group (HFD), and the high-fat diet switching to normal chow diet group (HFD-NCD), with an intervention duration of 12 months. Body weight and glucose tolerance were monitored throughout the intervention period. F-DPA714 PET/CT imaging was performed at 3, 6, and 12 months to detect cerebral TSPO signals. At the end of the experiment, hippocampal microglial activation (IBA1/TSPO), neuronal apoptosis (TUNEL), hippocampal neuronal integrity and structural damage (Nissl staining,β-III-tubulin, NeuN), and the expression of pro-inflammatory factors including TNF-α were measured. Additionally, behavioral tests were conducted to assess affective and cognitive functions of the mice. RESULTS: The HFD group presented with obesity and signs of metabolic syndrome, accompanied by progressive elevation of cerebral TSPO signals, microglial activation, upregulated expression of inflammatory factors, increased neuronal apoptosis, reduced intensity of hippocampal Nissl bodies, downregulated β-III-tubulin expression, and decreased NeuN-positive neuron counts in the CA3, CA1, and DG subregions, as well as depressive-like behaviors and cognitive impairment. In contrast, metabolic disorders, neuroinflammation, and behavioral deficits were significantly ameliorated in the HFD-NCD group. Dietary intervention also improved neuronal metabolic disturbance and partially protected neuronal structure and quantity, but failed to fully restore damaged neurons to normal levels. Correlation analysis revealed that TSPO imaging indices were strongly positively correlated with inflammatory biomarkers, and negatively correlated with Nissl staining, β-III-tubulin expression, and NeuN-positive neuron counts, reflecting the link between neuroinflammation and neuronal damage. CONCLUSION: Obesity induced by long-term high-fat diet can trigger neuroinflammation, neuronal structural impairment and loss, and associated brain function impairment, and these alterations can be effectively attenuated but not completely reversed via dietary intervention. TSPO-PET/CT serves as a reliable tool for non-invasive monitoring of the dynamic progression and reversal of neuroinflammation in this context.
Neurovascular unit dysfunction in vascular cognitive impairment: Mechanisms, biomarkers, and translational strategies.
Hoyer-Kimura C, Hay M
Exp Neurol · 2026 Sep · PMID 42105801 · Publisher ↗
Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is...
Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is highly prevalent and frequently coexists with Alzheimer's disease pathology. Despite this, it remains poorly defined in clinical practice and lacks approved disease-modifying therapies. Therapeutic development has been hindered by biological heterogeneity, challenges in patient stratification, and a historical emphasis on neurodegenerative targets that inadequately address vascular mechanisms. Increasing evidence implicates dysfunction of the neurovascular unit-including small vessel disease, chronic hypoperfusion, blood-brain barrier disruption, and neuroinflammation-as a central driver of vascular-mediated cognitive impairment and a unifying therapeutic target across diverse VCID phenotypes. In this review, we synthesize current understanding of VCID pathobiology with a focus on neurovascular unit dysfunction and emerging mechanism-based strategies aimed at restoring vascular and neurovascular homeostasis. We further examine translational considerations for targeting neurovascular signaling pathways, including endothelial stabilization, modulation of vascular inflammation, and preservation of blood-brain barrier integrity. As an illustrative example, we discuss preclinical evidence supporting Mas receptor agonism, including the glycosylated angiotensin-(1-7) analogue PNA5, as a potential approach to address vascular-mediated cognitive impairment. Finally, we explore implications for biomarker selection, patient enrichment, and early clinical trial design. Together, this framework highlights neurovascular dysfunction as a tractable therapeutic target in VCID and underscores the need for mechanism-driven approaches to address a substantial unmet clinical need.
Aquaporin-4 depolarization in stroke: Mechanisms and therapeutic implications.
Xiong H, Yang L, Liao Z … +3 more , Li Y, Zhang W, Mei Z
Exp Neurol · 2026 Sep · PMID 42103207 · Publisher ↗
Cerebral edema is a life-threatening complication of stroke, yet its underlying mechanisms remain incompletely understood, hindering the development of effective therapies. Aquaporin-4 (AQP4), the principal water channel...
Cerebral edema is a life-threatening complication of stroke, yet its underlying mechanisms remain incompletely understood, hindering the development of effective therapies. Aquaporin-4 (AQP4), the principal water channel of the glymphatic system, is crucial for cerebral water homeostasis. Following a stroke, AQP4 undergoes pathological depolarization-a loss of its polarized localization on astrocytic endfeet. This review establishes AQP4 depolarization as a central, unifying event that orchestrates secondary brain injury in stroke. We systematically dissect how AQP4 depolarization disrupts both glymphatic clearance and blood-brain barrier (BBB) integrity, thereby fueling a vicious cycle of edema formation. A key insight we advance is the divergent pathophysiology between stroke subtypes: in ischemic stroke, AQP4 depolarization drives initial glymphatic failure and cytotoxic edema, which subsequently promotes BBB breakdown and vasogenic edema. Conversely, in hemorrhagic stroke, primary vasogenic edema triggers AQP4 depolarization, which then mediates secondary glymphatic impairment and cytotoxic edema. Based on this mechanistic framework, we critically evaluate emerging interventions aimed at preserving AQP4 polarity. We conclude that maintaining AQP4 polarization, rather than non-selectively inhibiting its channel function, represents a paradigm shift and a more precise neuroprotective strategy for combating stroke-induced cerebral edema.
Variability-dominated auditory cortical dysfunction and targeted VNS modulation in a Mecp2 model of Rett syndrome.
Tahmasebi G, Adcock KS, Engineer CT
Exp Neurol · 2026 Sep · PMID 42103206 · Publisher ↗
OBJECTIVE: Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-linked transcriptional regulator MECP2, which causes widespread abnormalities in cortical network activity and sensory processing. In...
OBJECTIVE: Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-linked transcriptional regulator MECP2, which causes widespread abnormalities in cortical network activity and sensory processing. In rodent models, Mecp2 rats recapitulate key clinical features of Rett syndrome, including disrupted auditory cortical responses and impaired spike timing fidelity. Given its potential to normalize abnormal cortical activity, vagus nerve stimulation (VNS) may offer a promising therapeutic approach. This study examined auditory local field potential (LFP) responses in Mecp2 rats and assesses the modulatory effects of VNS. METHODS: Auditory cortical LFPs were recorded in response to speech, noise, and tone stimuli in Mecp2 rats, VNS-treated Mecp2 rats, and wild-type littermates. LFP component latency, amplitude, trial-to-trial variability, and oscillatory band power were quantitatively analyzed across groups. RESULTS: Mecp2 rats were characterized by delayed and weakened LFP responses, widespread increases in trial-to-trial variability of latency, amplitude, and power, and stimulus-dependent changes in spectral power, with the most pronounced abnormalities for speech, followed by tones and then noise. VNS partially normalized these abnormalities by improving speech-evoked latency and variability and reducing noise-evoked power variability. However, tone-evoked responses were largely unchanged with VNS, indicating a selective rescue of specific components and stimulus classes rather than a global restoration of auditory function. These findings demonstrate robust auditory cortical processing deficits in a preclinical model of Rett syndrome and highlight the potential of VNS to partially restore cortical function. The results support further development of targeted neuromodulatory interventions to ameliorate sensory processing abnormalities in Rett syndrome.
Chronic activation of corticospinal tract neurons after pyramidotomy injury enhances neither behavioral recovery nor axonal sprouting.
Wang Z, Brannigan M, Friedrich L … +1 more , Blackmore MG
Exp Neurol · 2026 Sep · PMID 42103205 · Full text
Modulation of neural activity is a promising strategy to influence the growth of axons and improve behavioral recovery after damage to the central nervous system. The benefits of neuromodulation likely depend on optimiza...
Modulation of neural activity is a promising strategy to influence the growth of axons and improve behavioral recovery after damage to the central nervous system. The benefits of neuromodulation likely depend on optimization across multiple input parameters. Here we used a chemogenetic approach to achieve continuous, long-term elevation of neural activity in murine corticospinal tract (CST) neurons. To specifically target CST neurons, AAV2-retro-DIO-hM3Dq-mCherry or matched mCherry control was injected to the cervical spinal cord of adult Emx1-Cre transgenic mice. Pilot studies verified efficient transgene expression in CST neurons and effective elevation of neural activity as assessed by cFos immunohistochemistry. In subsequent experiments mice were administered either DIO-hM3Dq-mCherry or control DIO-mCherry, were pre-trained on a pellet retrieval task, and then received unilateral pyramidotomy injury to selectively ablate the right CST. Mice then received continual clozapine via drinking water and weekly testing on the pellet retrieval task, followed by cortical injection of a viral tracer to assess cross-midline sprouting by the spared CST. After sacrifice at eight weeks post-injury immunohistochemistry for cFos verified elevated CST activity in hM3Dq-treated animals and immunohistochemistry for PKC-gamma verified unilateral ablation of the CST in all animals. Despite the chronic elevation of CST activity, however, both groups showed similar levels of cross-midline CST sprouting and similar success in the pellet retrieval task. These data indicate that continuous, long-term elevation of activity that is targeted specifically to CST neurons does not affect compensatory sprouting or directed forelimb movements.
The TAK1-YAP Axis synergistically suppresses oxidative stress and apoptosis via a non-canonical signaling pathway: A neuroprotective mechanism in ischemic stroke.
Pan E, Chen J, Xin Y … +7 more , Gao Y, Dong J, Xu Y, Zhou J, Zhou X, Chen H, Zhao P
Exp Neurol · 2026 Sep · PMID 42103204 · Publisher ↗
Ischemic stroke (IS) is one of the leading causes of global disability and mortality, yet effective treatments targeting oxidative stress (OS) and neuronal apoptosis remain lacking. This study investigates the neuroprote...
Ischemic stroke (IS) is one of the leading causes of global disability and mortality, yet effective treatments targeting oxidative stress (OS) and neuronal apoptosis remain lacking. This study investigates the neuroprotective role of Yes-associated protein (YAP) in IS and its regulatory mechanisms. Using clinical IS patient serum samples, a mouse middle cerebral artery occlusion (MCAO) model, and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model, we found that YAP protein levels were significantly downregulated post-ischemia, correlating with aggravated OS and neuronal apoptosis. Overexpression of Yap1 via adeno-associated virus (AAV) vectors reduced infarct volume, restored cerebral blood flow, and improved neurological and cognitive functions in MCAO mice. Mechanistically, YAP alleviated oxidative damage by enhancing the activity of antioxidant enzymes (e.g., GSH-Px, SOD) and inhibited apoptosis, as validated by TUNEL and Annexin V/PI assays. Intriguingly, under ischemic conditions, YAP phosphorylation was regulated by TAK1 rather than the canonical Hippo signaling pathway. Knockdown of TAK1 synergized with YAP activation to mitigate oxidative damage and neuronal apoptosis. These findings reveal the critical neuroprotective role of YAP in IS and identify the TAK1-YAP interaction as a therapeutic target. This study provides a mechanistic foundation for developing YAP-based interventions for IS.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe