Acta Neuropathologica Communications最新文献

Extracranial metastasis of IDH-wildtype glioblastoma is very rare and poorly understood at the molecular level. We report a case of FGFR3::TACC3 fusion IDH-wildtype glioblastoma in a 61-year-old male, whose preoperative blood sample showed highly aberrant cfDNA fragmentation patterns, which could be suggestive of early systemic dissemination, undetected by standard-of-care imaging of his body. Eleven months post-resection and adjuvant therapy, he developed widespread extracranial metastases. Comprehensive molecular profiling of matched primary and metastatic tumors revealed broadly conserved genomic, transcriptomic, and copy number landscapes, with the metastasis harboring an additional ERCC6 deletion and enriched expression of receptor tyrosine kinase signaling genes. These findings provide rare insight into the genetic continuity and evolution underlying IDH-wildtype glioblastoma metastasis.

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by a poor prognosis and a manifestation within the first 2 years of life. Genetic hallmark of these tumors is the homozygous inactivation of SMARCB1 or, in some rare cases, of SMARCA4. While heterozygous pathogenic variants of SMARCA4 have been described, inter alia, in the context of other CNS malignancies such as medulloblastoma or glioblastoma, the co-occurrence of pathogenic variants in both, SMARCB1 and SMARCA4, in the same AT/RT has to our knowledge not been reported previously. Liquid biopsy, a rapidly developing and promising technique measuring cell-free DNA (cfDNA) in body fluids such as the cerebrospinal fluid (CSF), offers a minimally invasive method to assess disease status. It has yet to be established as a standard procedure in the diagnostic workup of CNS tumors. We present the case of a three-year-old male diagnosed with an AT/RT that exhibits both biallelic alterations of SMARCB1 due to a frameshift mutation and loss of heterozygosity as well as a heterozygous missense variant in SMARCA4 presenting with early disease progression. We employed liquid biopsy successfully to monitor disease progression throughout treatment and the subsequent relapse. We highlight the ramifications that simultaneous alterations in two chromatin-modifying genes may have for tumor biology and clinical course.

Macrophages are crucial for neuroinflammatory responses following traumatic brain injury (TBI), encompassing various subtypes, such as border-associated macrophages (BAMs) that contribute to both brain damage and repair. However, the pathophysiological relevance of subtype-specific molecular markers is poorly understood. This study investigated the role of the BAM marker mannose receptor C-type 1 (MRC1, also known as CD206) during the early phase of TBI using controlled cortical impact (CCI). MRC1 gene expression was up-regulated, peaking between 3 to 7 days post-injury (dpi), and MRC1 protein expression predominantly localized to BAMs. To assess pathophysiological relevance, MRC1-deficient (MRC1-KO) and wild-type littermates (MRC1-WT) were examined following CCI for early neurological deficits, brain structural damage, intracerebral hematoma, and neuroinflammatory marker expression. At 5 dpi, MRC1-KO mice showed increased brain lesion volume and hippocampal neuron loss, with minor differences in neurological deficits compared to MRC1-WT mice. Intracerebral hematoma size increased in male but remained unchanged in female MRC1-KO mice. Immunostaining revealed no genotype-specific effects on GFAP⁺ astrocytes, while the number of perilesional CD68⁺ macrophages/microglia were reduced in MRC1-KO mice. Analysis of neuroinflammatory gene markers revealed an overall reduction in MRC1-KO mice. Sex-specific regulation was observed for the M2-like macrophage/microglia marker Arg1, with decreased expression in male and increased expression in female MRC1-KO compared to MRC1-WT mice. In conclusion, lack of MRC1 exacerbated brain tissue damage following experimental TBI. Reduced CD68+ macrophages/microglia and neuroinflammatory marker expression suggests impaired neuroinflammatory response in MRC1-KO, indicating MRC1 expression on BAMs contributes to beneficial early neuroinflammatory response following TBI.

Soluble tau oligomeric assemblies display neurotoxic properties and may provide a pathogenic link between neurofibrillary tangle evolution and selective neuronal vulnerability in Alzheimer's disease (AD). However, the precise molecular and cellular pathways mediating tau oligomer toxicity are unclear. We combined single-neuron laser capture microdissection with custom microarrays to investigate differences in the molecular signatures of basal forebrain neurons within the nucleus basalis of Meynert (nbM) labeled for p75^NTR, a cholinergic cell marker, or dual-labeled for p75^NTR and TOC1, a tau oligomer marker. Tissue was obtained postmortem from Rush Religious Orders Study participants who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Using clinical diagnosis as a covariate to isolate tau oligomer-specific mechanisms, we identified 140 differentially expressed genes (DEGs) in p75^NTR + /TOC1 + cholinergic nbM neurons compared to p75^NTR + /TOC1- neurons. STRING interactome and pathway analysis revealed that downregulated genes were associated with pre- and postsynaptic function, with additional enrichment in glutamate and acetylcholine signaling. By contrast, upregulated genes related to cellular stress responses and apoptosis were clustered with a subset of downregulated DEGs regulating mitochondrial metabolism and redox function, indicative of bioenergetic failure. Weighted gene co-expression correlation network analysis of the entire dataset revealed only two significantly correlated modules, which were either negatively correlated with the presence of TOC1 and enriched for synaptic signaling or positively correlated with TOC1 and enriched for cellular responses to hypoxia. These data show with single-neuron resolution that oligomeric tau formation in vulnerable cholinergic nbM neurons, even prior to MCI, is associated with the dysregulation of multiple classes of genes driving cell/mitochondrial stress and synaptic imbalances, which may be amenable for disease-modifying therapeutic approaches.

Vascular contributions to cognitive impairment and dementia (VCID) are one of the leading causes of dementia, where reactive astrogliosis, blood-brain barrier (BBB) disruption, and white matter lesions (WML) are the key features. However, the molecular and cellular mechanisms underlying VCID are not well understood. Na-K-Cl cotransporter 1 (NKCC1) activation via its upstream regulatory kinase SPAK (STE20/SPS1-related proline/alanine-rich kinase) causes intracellular Na⁺ overload, hypertrophy, and astrogliosis, a cascade that has been implicated in VCID. In this study, we investigated whether treatment with the SPAK inhibitor ZT-1a at the symptomatic stage in a VCID mouse model is effective in reducing reactive astrogliosis and BBB breakdown, and in improving cerebral blood flow (CBF). VCID was induced in adult C57BL/6J mice using bilateral carotid artery stenosis (BCAS), and either Vehicle (Veh, DMSO) or ZT-1a was administered from weeks 4 to 8 post-BCAS. CBF was monitored by laser speckle imaging, and cognitive deficits were assessed using the Morris water maze test. BBB integrity, astrocytic endfeet coverage, and demyelination were assessed by immunofluorescence (IF) analysis. BCAS mice exhibited a biphasic reduction of CBF and cognitive impairments, parallel with a significant loss of myelin basic protein (MBP) in white matter tracts. Increased expression and phosphorylation of NKCC1 were detected in GFAP⁺ astrocytes and Iba1⁺ microglia/macrophage following BCAS. Reduced ZO-1, Claudin-5, and AQP4 expression in vessels and extravasation of serum albumin into the brain parenchyma in BCAS mice indicate the loss of BBB integrity. Importantly, ZT-1a treatment of the BCAS mice significantly improved CBF recovery and prevented the learning and memory deficit. These mice displayed reduced astrogliosis, microglial activation, MMP-2/9 expression, BBB damage, and axonal demyelination. Our results strongly suggest that hypoperfusion-induced SPAK-NKCC1 activation contributes to reactive astrogliosis, BBB disruption, CBF reduction, and cognitive impairment. The SPAK-NKCC1 complex represents a modifiable therapeutic target for counteracting VCID progression.

The occurrence and extent of central nervous system (CNS) fiber tract inflammation in chronic-phase intracerebral hemorrhage (ICH) patients are not well understood due to the heterogeneity of Wallerian degeneration (WD). This study aims to investigate the presence of CNS fiber tract inflammation in chronic-phase ICH patients and to characterize any inflammatory cells in the fiber tract. An in vivo translocator protein (TSPO)-PET study was undertaken in 22 ICH patients over 6 months after stroke who were admitted to the First Affiliated Hospital of Fujian Medical University or Tianjin Medical University General Hospital from April 2017 to June 2020. Twenty-three healthy controls or participants with various CNS diseases were included. Cerebral peduncle (CP) TSPO uptake was calculated as the average standardized uptake value ratio (SUVr). To aid interpretation of the TSPO uptake results at the CNS fiber tract level, spatial transcriptome sequencing was used to identify fiber tract inflammation in an ICH mouse model at 4wks post-onset and to characterize the cells present in the inflamed fiber tract. PET imaging showed that CP TSPO SUVr values in patients over 6 months since ICH were higher than in healthy controls (mean CP SUVr ± SD; ICH: 1.19 ± 0.11; control: 1.02 ± 0.08; P < 0.0001), and there was an obvious negative correlation between CP TSPO uptake and CP volume, which means that the CNS fiber tract inflammation persists and is still active in chronic-phase ICH patients, which may worsen their prognosis. Spatial transcriptome sequencing of the CNS fiber tract in ICH model mice identified a population of peripheral-derived pro-inflammatory macrophages contributing to the increased TSPO uptake. CP uptake was associated with frontal bone marrow uptake according to association analyses, indicating the cells possibly extending from the skull bone marrow into CNS in the chronic phase.

Mutations or polymorphisms in GRN, encoding the CNS glycoprotein progranulin (PGRN), have been linked to several neurodegenerative diseases. In this study, we explored the role of PGRN in prion diseases. We observed that prion infection upregulated microglial PGRN expression. Following intracerebral inoculation with RML6 prions, Grn^-/- mice exhibited accelerated disease progression compared to Grn^+/- and Grn^+/+ littermates. Histological analysis revealed augmented microglial activation in Grn^-/- mice. Temporal analysis revealed enhanced early microglial activation and prion clearance at 120 dpi, followed by excessive complement activation but inadequate clearance by 150 dpi. Additionally, Grn^-/- brains exhibited exacerbated astrogliosis and vacuolation. RNA-seq analysis indicated that complete PGRN deficiency in prion-infected mice shifted microglia from homeostatic to pro-inflammatory states. Notably, microglia-specific depletion of PGRN did not affect prion pathogenesis, suggesting that PGRN deficiency affects microglial activation and prion progression in a non-cell autonomous manner. These findings suggest that microglia respond to prion infection in a stepwise manner, and PGRN plays a critical role in modulating prion-induced microglial activation. Our results highlight the neuroprotective role of PGRN in prion disease and suggest that supplementation or boosting expression of PGRN could represent a promising therapeutic strategy.

White adipose tissue (WAT) has a crucial role in maintaining systemic energy homeostasis. Numerous biological pathway studies have highlighted the importance of adipokines in regulating metabolic pathways and contributing to metabolic dysfunction in animal models and patients with ALS. Despite these associations, the specific molecular mechanisms remain poorly understood. Moreover, the direct contribution of WAT to the energy metabolism abnormalities observed in ALS has yet to be clearly defined. The current study sought to identify perturbances in WAT, main source of leptin, during the clinical course of the disease in TDP-43^A315T mice using histological, proteomic, and molecular biological techniques. We present the first evidence of a significant histological alteration in WAT prior to the symptomatic stage of the disease in TDP-43^A315T mice, providing novel insights into pathological features earlier in the onset of symptoms, and showing WAT as a target organ for ALS. In human ALS cases, we found that circulating leptin levels at the time of diagnosis were lower in the plasma of men with ALS who were overweight or obese and had rapidly progressive ALS, emphasizing the importance of considering sex-specific approaches when analysing adipokines essential for body weight control.

Excessive glutamate receptor activation during brain pathologies causes varicose dendritic swelling, also known as "dendritic beading", yet its impact on developing brain circuits is poorly understood. Using field electrophysiology and two-photon imaging in awake, behaving mice and acute brain slices (P11-19), we found that severe and recurrent seizure-like activity (induced by NMDA and 4-aminopyridine) resulted in widespread, long-lasting dendritic beading and spine loss in cortical and hippocampal neurons, with localization patterns distinct from those described in adults. Beads showed persistently high calcium levels and stopped the spread of dendritic calcium signals. Dendritic beads suppressed hippocampal evoked field potentials, followed by only partial recovery, and reduced hippocampal long-term potentiation. Clinically used hyperosmotic treatments (mannitol or hypertonic saline) reduced seizure-induced beading and restored dendritic signal propagation. These findings suggest that seizure-induced dendritic beading disrupts circuit function and synaptic plasticity and may contribute to cognitive deficits after early-life seizures.