Alzheimer disease (AD) pathology affects the transentorhinal/entorhinal region early but whether entorhinal cortex (EC) astrocytes are causal drivers or therapeutic targets remains unresolved. This narrative review evaluates EC astrocytes through an explicit evidence hierarchy. We distinguish: (1) human EC-specific neuropathology, imaging, and transcriptomic findings, (2) human AD astrocyte data lacking EC-cell resolution, (3) mechanistic evidence from animal and cellular models, and (4) translational hypotheses. Human data support early EC vulnerability and region- and stage-dependent astrocyte remodeling, whereas the most direct functional evidence comes from rodent medial EC layer II and should be interpreted as circuit plausibility rather than anatomical equivalence to the human EC. We therefore prioritize candidate astrocyte modules according to astrocyte specificity, relevance to EC or medial temporal pathology, mechanistic links to circuit dysfunction, and the availability of measurable target-engagement readouts. These modules include inflammatory-complement signaling, EAAT2/GLT-1-mediated glutamate clearance, MAO-B/GABA metabolism, AQP4-related gliovascular regulation, astrocytic calcium signaling, and APOE-related lipid handling. Cell transplantation, glial reprogramming, and engineered extracellular vesicles remain experimental platforms. EC astrocytes should therefore be viewed as candidate circuit-glial vulnerability nodes requiring human validation, not as established clinical targets.
Repetitive mild traumatic brain injury (r-mTBI) is strongly associated with the increased risk of developing neurodegenerative diseases. Previously, we have revealed the histopathological, biochemical, and transcriptional changes following exposure to chronic r-mTBI in wild-type (WT) mice. Herein, we performed a complementary electron microscopy analysis in a young adult (3-month-old) WT cohort to reveal the ultrastructural changes observed 3 months following chronic r-mTBI. Additionally, because age at injury has been associated with an increased risk for poorer outcomes after TBI, an older WT cohort (12-month-old, middle-aged) was included to determine this relationship. While the cortical grey-matter exhibited minimal ultrastructural abnormalities after r-mTBI, we observed prominent TBI-related changes in the corpus callosum, including increased axonal g-ratios and higher density of degenerating axons in both cohorts. However, no age-dependent injury differences were observed across measured parameters, except for a notable TBI-dependent increase in phagolysosome-bearing perivascular cells within the corpus callosum of injured aged mice compared to younger TBI counterparts. Collectively, these findings suggest that chronic r-mTBI in young adulthood and middle age produces similar white matter ultrastructural changes 3 months after r-mTBI. Future studies are warranted to determine whether ultrastructural differences emerge with injuries administered earlier in life or at advanced age.
Encephalitic alphaviruses such as Western equine encephalitis virus (WEEV) result in significant morbidity through acute viremia and postencephalitic neurologic dysfunction. Viral neurotropism is linked to chronic glial-mediated neuroinflammation and increased risk for neurodegenerative disorders including Alzheimer disease and Parkinson disease. We previously showed that sublethal WEEV infection induces nigrostriatal gliosis, neuronal loss, and Parkinsonian-like motor deficits in mice. However, the temporal progression of glial activation and neurodegeneration in brain regions relevant to dementia remains unclear. To address this, we performed a longitudinal assessment of hippocampal pathology following intranasal infection with McMillan WEEV. Brain tissue was collected at 1, 2, and 4 weeks postinfection and analyzed using high-content fluorescence imaging, deep learning-based image analysis, and population-level cellular phenotyping. We observed a marked increase in gliosis peaking at 1-week postinfection, coinciding with fibrotic, immune cell-dense lesions that inversely correlated with eosinophilic neuronal density. Automated skeletonization analysis revealed increased astrocyte reactivity and a predominantly bushy microglial morphology at this time point. Heat map densitometry further demonstrated progressive amyloid-β accumulation across all time points. Together, these findings define a dynamic sequence of glial activation, lesion formation, and protein aggregation underlying WEEV-induced hippocampal neurotoxicity.
Biallelic pathogenic variants in SORD (Sorbitoldehydrongenase gene), encoding sorbitol dehydrogenase, are a common cause of autosomal recessive axonal Charcot-Marie-Tooth disease type 2 (CMT2). Recent evidence suggests direct involvement of skeletal muscle in addition to peripheral nerve degeneration. We investigated muscle biopsies from 4 genetically confirmed CMT-SORD patients using an integrative approach. Histological evaluation revealed features of chronic denervation with grouped fiber atrophy, fiber-type grouping and central nuclei, ie, non-specific neurogenic muscle atrophy. Ultrastructural studies demonstrated mitochondrial abnormalities and expansion of the sarcoplasmic reticulum (SR). Proteomic profiling identified 220 significantly dysregulated proteins in CMT-SORD muscle, including alterations in mitochondrial complex I components, redox enzymes, and metabolic regulators distinct from changes observed in other rare recessive CMTs. Quantitative PCR validated increased levels of NNMT, POSTN, TACO1, as well as complement and immunomodulatory factors, suggesting mitochondrial stress, compensatory metabolic activation and tissue remodeling. Despite mitochondrial vulnerability, serum studies indicated that GDF-15 and FGF-21 did not appear to be suitable biomarkers for CMT-SORD. These findings demonstrate that SORD deficiency induces molecular and structural changes in skeletal muscle that extend beyond denervation, implicating impaired sorbitol metabolism, oxidative stress, and mitochondrial dysfunction as intrinsic myopathic features of SORD-related CMT2. They indicate the need for therapeutic strategies targeting both neuronal and muscular compartments.
Temporal lobe epilepsy (TLE) secondary to hippocampal sclerosis (HS) is a common cause of drug-resistant epilepsy. HS is characterized by neuronal loss in selected hippocampal subfields and gliosis. Age at epilepsy onset (AEO) critically influences disease severity and treatment response. We compared early AEO (<10 years) and late AEO (>11 years) in hippocampi from patients undergoing surgery for HS (n = 30). HS hippocampi showed altered mitochondrial enzyme activities and membrane potential (vs controls). Early AEO showed reduced membrane potential and ATP and increased proton leak, whereas other activities did not differ significantly between early and late AEO. Altered proteomic profile of mitochondrial complexes, organization, and metabolic pathways was noted in early AEO. Astrocytic proteomics revealed altered markers of blood-brain barrier (BBB), apoptosis, and excitotoxicity in early AEO. Overexpression of aquaporins, BBB junction proteins, and ion channels suggests compensatory mechanisms in late AEO. Proteomics of hippocampal subfields revealed increased expression of antioxidant and synaptic proteins in dentate gyrus in late AEO, indicating neuroprotective mechanisms, whereas CA1 showed downregulation of glutamate receptors and mitochondrial proteins, consistent with neuronal death. Based on these results, we propose that early AEO-HS is associated with mitochondrial dysfunction, whereas non-mitochondrial factors are associated with late AEO-HS.
Meningiomas are the most common primary central nervous system tumors and their biological behavior is closely related to histopathological grade and proliferative activity. This study investigated the associations between World Health Organization (WHO) grade, tumor location, mitotic activity, and Ki-67 labeling index in previously untreated meningiomas. We retrospectively analyzed 298 surgically treated primary meningiomas diagnosed between 2013 and 2025, re-evaluated according to the 2021 WHO Classification of Central Nervous System Tumors. Mitotic counts and Ki-67 labeling indices were assessed in hotspot areas. Associations between proliferation markers, grade, and anatomical location were analyzed statistically, and receiver operating characteristic (ROC) analyses determined optimal cut-off values. Of the tumors, 55.0% were WHO Grade 1, 41.6% Grade 2, and 3.4% Grade 3. Both markers increased significantly with grade and showed a strong positive correlation (ρ = 0.79, P < .001). Convexity meningiomas were associated with higher grades and increased proliferative activity, whereas skull base and spinal tumors predominantly exhibited lower grades and lower proliferation indices. ROC analyses demonstrated comparable discriminatory performance for Ki-67 and mitotic counts across WHO grades. In summary, proliferation markers strongly correlate with WHO grade and vary by tumor location, supporting their combined value in meningioma risk stratification.
Hydroxychloroquine (HCQ), chloroquine (CQ), and colchicine are widely used to treat autoimmune and inflammatory diseases but can cause toxic autophagic vacuolar myopathies. This study investigates the pathological mechanisms of HCQ/CQ- and colchicine-induced myopathies through integrated clinical, histopathological, ultrastructural, and proteomic analyses. Nine patients with clinicopathologically defined toxic myopathy (HCQ/CQ, n = 4; colchicine, n = 5) were included. Muscle biopsies were analyzed using histoenzymology, immunohistochemistry for autophagic and immune markers, electron microscopy, and proteomic profiling in selected cases. Clinically, both groups presented with proximal muscle weakness and myalgia after variable drug exposure. Histology revealed rimmed and non-rimmed vacuoles, especially in HCQ/CQ cases, and myofibrillar disorganization; the latter predominated in colchicine-treated patients. Electron microscopy confirmed myofibrillar disruption in colchicine-treated patients and autophagosomes with curvilinear bodies in HCQ/CQ cases. Immunohistochemistry showed MHC-I upregulation, heterogeneous C5b-9 deposition, and accumulation of LC3 and p62, with evidence of endoplasmic reticulum stress and transcriptional dysregulation by GRP170 overexpression and cytoplasmic MeCP2 redistribution. Proteomic analysis revealed a shared molecular signature involving immune activation, extracellular matrix remodeling, cytoskeletal stress, mitochondrial dysfunction, and dysregulation of the autophagy-lysosome pathway. Overall, HCQ/CQ- and colchicine-induced myopathies converge on common mechanisms of autophagic impairment, immune activation, and disrupted muscle homeostasis.
TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons leading to muscle weakness, paralysis, and ultimately, respiratory failure. Extracellular vesicles (EVs) facilitate intercellular communication by mimicking the functions of their parent cells. In this study, we found that repeated administration of neural stem cell-derived extracellular vesicles (NSC-derived EVs) improved motor performance and provided protection to lumbar motor neurons, the neuromuscular junctions, and muscle morphology in the SOD1 G93A transgenic mouse model of ALS. Furthermore, by analyzing the RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated that the rescue effects of NSC-derived EVs might be linked to the p53 pathway. Compared to the PBS control treatment group, both TP53 and the p53 upregulated modulator of apoptosis (PUMA) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data provide additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS.
Neuronal central chromatolysis (CC) is the histopathological hallmark of pellagra encephalopathy, a neurological deficit resulting from vitamin deficiencies. Pellagrous CC neurons are morphologically similar to ballooned achromatic neurons in other conditions but the distinct pathomechanisms remain unclear. We performed a clinico-neuropathological analysis of 10 autopsy cases of pellagra encephalopathy. The pellagra encephalopathy cases were immunohistochemically compared with disease controls, including cases of axonal injury and neurodegenerative diseases. Electron microscopic evaluation and immunohistochemical examinations targeting mitochondrial fragmentation were performed for a representative case. Four of 10 pellagra encephalopathy patients exhibited prolonged impairment of consciousness distinguishable from alcohol withdrawal delirium. Pellagrous CC neurons were negative for cytoskeletal markers whereas ballooned achromatic neurons in the disease control cases were positive. Immunohistochemical analysis of mitochondrial markers revealed that CC neurons exhibited more intense immunoreactivity for COX-IV and mitochondrial fissure factor compared to the disease controls. Transmission electron microscopy of these CC neurons revealed a marked increase in the mitochondria with amorphous densities. These findings indicate that the pathomechanism of pellagrous CC is distinct from that of the ballooned achromatic neurons of other etiologies. Mitochondrial alterations in pellagrous CC neurons suggest that neuronal energy deficits resulting from nicotinamide adenine dinucleotide deficiency induce mitochondrial fragmentation.
Somatic mutations affecting endothelial signaling pathways have emerged as important contributors to brain arteriovenous malformations (bAVMs). Although activating mutations in the RAS/MAPK pathway have been frequently reported, alternative molecular mechanisms remain incompletely understood. We describe 2 autopsy-confirmed bAVMs harboring somatic PIK3CA mutations, including one case with a concurrent PTEN alteration. Histologically, both lesions demonstrated typical bAVM architecture without unusual structural features. Immunohistochemical analysis revealed lesion-restricted activation of the PI3K/AKT/mTOR pathway in endothelial cells; adjacent normal vessels were negative. In contrast, ERK phosphorylation was focal and limited; targeted sequencing did not identify pathogenic RAS/MAPK mutations. These findings suggest dominant PI3K pathway activation with secondary or limited MAPK engagement. Variant allele frequencies were interpreted cautiously owing to whole-genome amplification from autopsy-derived tissue. In one case, prior Gamma Knife radiosurgery was considered to have contributed to the findings but histological features of radiation-associated vascular injury were not observed. Together, these findings support molecular heterogeneity in bAVMs and suggest that PIK3CA-driven PI3K pathway activation may contribute to vascular remodeling in RAS-negative lesions. Correlation of molecular alterations with pathway-specific endothelial activation highlights the value of integrated genetic and pathological assessment in bAVMs.
YAP1 fusions are well documented in pediatric central nervous system (CNS) tumors, particularly in supratentorial ependymomas and meningiomas where they are generally associated with a favorable prognosis. Outside these entities, YAP1 fusions have rarely been reported in gliomas or other high-grade neuroepithelial tumors. Here, we describe 2 high-grade neuroepithelial tumors harboring a recurrent YAP1::MAML2 fusion. Comprehensive histopathologic evaluation, immunohistochemistry, whole-exome sequencing using the SimcereDx neuro-oncology panel, and DNA methylation profiling were performed. Both tumors were IDH- and H3-wildtype and lacked canonical alterations in the RTK, TP53, or MAPK pathways. DNA methylation profiling did not match any established CNS tumor class. Histologically, both tumors demonstrated rhabdoid morphology accompanied by a prominent inflammatory microenvironment enriched in CD68- and CD163-positive macrophages. Despite sharing the same fusion event, the 2 tumors exhibited divergent morphologic and immunophenotypic features, indicating substantial heterogeneity. These findings suggest a potentially distinct, molecularly defined tumor subgroup characterized by YAP1::MAML2 fusion, high-grade neuroepithelial morphology, rhabdoid features, and an inflammatory microenvironment. They highlight the limitations of current methylation-based classification for such rare entities. Accurate diagnosis requires an integrated approach incorporating histologic features, clinical context, immunophenotype, and molecular alterations.
Meningiomas are central nervous system tumors primarily treated by surgery and/or radiation with large variance in progression-free survival. Emerging molecular diagnostics such as circular RNA (circRNA) profiling show potential for enhancing diagnostic accuracy but are limited by the processing workflows associated with traditional fresh-frozen protocols that may lead to biomarker degradation. The NICO Automated Preservation System (APS) is a surgical tool that aspirates and resects intact tumor cores, quickly storing the removed tissue in a refrigerated environment of Ringer's Lactate fluid. To overcome the challenge of obtaining and preserving tissue for molecular diagnostics, we sought to test the extent to which the NICO APS enhances tissue preservation versus traditional protocols in 20 meningioma resections; we focused on circRNA profiles as potential clinical biomarkers. The NICO APS enhanced RNA integrity (P = .0023), yielding high-quality data (>Q30 median = 95%), which reduced the variation of circRNA detection. Weighted Gene Co-expression Network Analysis identified a total of 4 modules highlighting NICO and traditional protocols and meningioma grades. Modules belonging to WHO grade 2 meningiomas may be associated with cellular metabolism and epitranscriptomic regulation. Our results show that circRNA detection is highly improved using NICO APS.
Accumulating evidence indicates that tripartite motif-containing protein 32 (TRIM32) has important functions in brain physiology and disease. This study investigated the role of TRIM32 in the development of epilepsy and its impact on synaptic remodeling. A rat model of epilepsy was established using pilocarpine with lithium chloride pretreatment and TRIM32 expression was examined by Western blotting and immunohistochemistry. The interaction between TRIM32 and BDNF was assessed by co-immunoprecipitation and immunofluorescence colocalization. TRIM32 knockdown in epileptic rats was achieved by shRNA transfection. Cognitive and anxiety-like behaviors were evaluated using the Y-maze and open-field tests; Western blotting was used to quantify the synaptic proteins PSD-95 and SYN and to assess activity of the BDNF/TrkB/CREB signaling pathway. TRIM32 expression was significantly reduced in epileptic rats. Moreover, TRIM32 knockdown aggravated epilepsy-associated cognitive deficits, impaired open-field performance, and exacerbated synaptic loss. Mechanistically, TRIM32 deficiency intensified these abnormalities through dysregulation of the BDNF/TrkB/CREB pathway. These data suggest that TRIM32 regulates synaptic protein expression in epilepsy and that its deficiency worsens anxiety-like behavior, cognitive impairment, and synaptic loss by perturbing BDNF/TrkB/CREB signaling, thereby providing insights that may inform future therapeutic strategies targeting this signaling pathway.
Ferroptosis has a crucial role in cerebral ischemia-reperfusion injury (IRI) but its potential modulation is a key challenge in the treatment of ischemic stroke. The function and mechanism of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) in neurological diseases, particularly its regulatory role in ferroptosis are unclear. We used a mouse model of transient middle cerebral artery occlusion (tMCAO/R) and a PC12 cell model of oxygen-glucose deprivation/reperfusion (OGD/R) to investigate the effects of virus-mediated gene knockdown of TRIM21. Effects were assessed using Western blotting, immunoprecipitation, biochemical assays, and behavioral tests. TRIM21 expression was significantly increased after cerebral IRI. Knockdown of TRIM21 improved neurological deficits, reduced cerebral infarct size, and suppressed inflammation. Knockdown of TRIM21 also inhibited ferroptosis and improved mitochondrial function whereas TRIM21 negatively regulated the p62-Keap1-Nrf2 pathway through ubiquitination of p62. Salvage experiments confirmed that Nrf2 is a key downstream molecule for the neuroprotective effects of TRIM21. The data indicate that TRIM21 inhibition of the Keap1-Nrf2 pathway through p62 ubiquitination exacerbated ferroptosis after ischemic stroke in the tMCAO/R model and suggest that targeted inhibition of TRIM21 holds promise as a novel strategy for treating ischemic stroke.
