Acta Neuropathologica Communications最新文献

We have evaluated the diagnostic potential of the seeding amplification assay (SAA) in detecting α-synuclein seeding activity in postmortem brain and cerebrospinal fluid (CSF) samples from patients with primary and co-pathology α-synucleinopathies. Moreover, we investigated potential SAA positivity in control samples which may suggest unrecognized co-pathology. A total of 15 brain and 14 CSF samples with definite dementia with Lewy bodies (DLB, n = 6), Alzheimer´s disease with amygdala Lewy body (AD/ALB, n = 3), and patients with concomitant Creutzfeldt-Jakob disease and Lewy body pathology (CJD/LBP, n = 6) comorbidity were tested for α-synuclein seeding activity using SAA assay utilizing recombinant α-synuclein (WT) with N-terminal His-tag. Control samples consisted of other neurodegenerative diseases (n = 17 for brain and n = 18 for CSF samples) and healthy corneal donors (n = 17). The analysis of seeding activity in brain samples suggested 100% sensitivity and 91.2% specificity. Five out of 34 brain control samples gave a positive SAA outcome. However, upon reevaluation, two of these samples were reclassified as Alzheimer´s disease (AD) with synucleinopathy co-pathology. The analysis of CSF also suggested 100% sensitivity and 94.4% specificity, although dilution of some samples was necessary to decrease the effect of inhibitors. We report a good performance of the SAA not only in postmortem samples from primary synucleinopathies with advanced pathology, but also in co-pathology synucleinopathies with isolated Lewy bodies in the amygdala in AD cases. Our findings highlight the importance of careful diagnostic evaluation in AD patients, where co-existing synucleinopathy may otherwise go unrecognized.

Brain invasion of meningioma is a controversial clinicopathological grading criterion that correlates with prognosis and is a stand-alone criterion for WHO grade 2 meningioma. Molecular correlates of meningioma cells and immune cell infiltration at the brain-meningioma border and its possible role in brain invasion are not known. We hypothesized that brain-invasive meningiomas have distinct gene expression profiles in meningioma cell populations and in tumour-associated microglia and macrophages (TAM) populations, most prominently at the brain-meningioma border.We performed spatial transcriptomics using NanoString GeoMx Digital Spatial Profiling to investigate the gene expression profiles of meningioma cell-enriched populations (Iba1-/CD68-) and TAM-enriched populations (Iba1+/CD68+) across 16 tumours. Regions of interest included core regions of meningiomas, the brain-meningioma border, and brain regions with confirmed invasion. Using an 1800 gene panel, we analysed differential gene expression across regions within each tumour and compared brain-invasive and non-invasive meningiomas.Meningioma cell-enriched populations from brain-invasive meningiomas (n = 8) showed significant upregulation of KRT18, implicated in filament reorganization, as well as genes involved in the cell cycle, glycolysis, and the growth factor receptor PDGFRB compared to non-invasive meningiomas (n = 8). Meningioma cell-enriched populations from the brain-meningioma border showed significant upregulation of KRT18, NDUFA4L2, and PKM relative to core areas. In TAM-enriched populations in brain tissue, we found upregulation of the chemokine receptor gene CSF1R relative to TAM-enriched populations in meningioma tissue and increased TAM infiltration in brain-invasive cases.In conclusion, our results demonstrate molecular changes in brain-invasive meningiomas compared to non-invasive meningiomas as well as spatial changes along the core-border axis. The expression pattern of TAMs also changed from meningioma to brain tissue. Additional studies are needed to confirm these findings and further reveal how we can target meningioma brain invasion.

TDP-43 proteinopathies, such as frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), are classified into five neuropathological subtypes, Types A to E, according to the morphology of TDP-43 inclusions. Recent cryo-electron microscopy analysis of FTLD-TDP cases demonstrated that TDP-43 filaments composing the inclusions are structurally different depending on the subtype, and remarkably, co-assembled heteromeric filaments of TDP-43 and annexin A11 (ANXA11) were identified in Type C. Therefore, the involvement of ANXA11 in TDP-43 proteinopathy should be further examined. Here, we pathologically and biochemically analyzed four cases of primary lateral sclerosis-phenotype FTLD/motor neuron disease (MND) with TDP-43 pathology (PLS-TDP), and found that ANXA11 co-localizes with FTLD-TDP Type A pathology in PLS-TDP. Immunoblot analysis of the PLS-TDP cases revealed that the banding patterns of C-terminal and chymotrypsin-resistant fragments of TDP-43 are distinct from those of FTLD-TDP Types A, B and C. In addition, the N-terminal fragments of ANXA11 appear to be different from those of FTLD-TDP Type C. Filaments extracted from PLS-TDP cases were TDP-43- and ANXA11-immunopositive, suggesting the presence of TDP-ANXA11 heteromeric filaments. These results suggest that co-aggregation of ANXA11 and TDP-43 may serve as a neuropathological and biochemical indicator distinguishing PLS from ALS in FTLD/MND.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) exhibit predominantly cytoplasmic phosphorylated inclusions of the protein TDP-43 as the major neuropathological lesion. Phosphorylated TDP-43 can modify protein aggregation and promote neuronal dysfunction and neurodegeneration in models of ALS and FTLD-TDP. The phosphatase calcineurin has previously been shown to directly dephosphorylate TDP-43 in vitro and prevent accumulation of phosphorylated TDP-43 in vivo in C. elegans. However, it is unknown whether dysregulation of calcineurin contributes to increased TDP-43 phosphorylation and neurodegeneration in the mammalian brain. Here we show in an inducible mouse model of ALS/FTLD-TDP driven by expression and cytoplasmic mislocalization of human TDP-43 (rNLS8 mice), calcineurin protein decreases dramatically in the brain. This depletion coincides with increased levels of the TDP-43 kinase CDC7 and accumulation of phosphorylated TDP-43, and precedes frank neurodegeneration. Using brain-wide single nucleus RNA sequencing (snRNAseq) in symptomatic rNLS8 mice, we find cell-type selective reduced expression of catalytic and regulatory subunits of calcineurin predominantly in GABAergic and glutamatergic neurons. In mouse primary neuron culture and C. elegans models of ALS/FTLD-TDP, we demonstrate activation or overexpression of calcineurin protects against accumulation of phosphorylated TDP-43, neurotoxicity, and neurodegeneration. Taken together, our data suggests calcineurin dysregulation may be a major contributor to loss of brain resilience mechanisms against phosphorylated TDP-43. Restoring calcineurin activity may present a new target for intervening in TDP-43 proteinopathies, including ALS and FTLD-TDP.

Regional distributions of amyloid-β (Aβ) and tau accumulation have provided important insights into the pathomechanisms of Alzheimer's disease (AD). While such analyses have typically been conducted through histochemical or clinical imaging studies, we previously reported unique regional associations among Aβ species, tau and other proteins by biochemically analyzing multiple postmortem brain regions. Here, using a new cohort and novel ELISAs, we investigated the regional relationships of Aβ species, tau, neuroglial markers, cathepsins and dipeptidyl peptidases (DPP) across AD stages. Despite a relatively small sample size, this study replicated key prior findings, including a strong regional association between Aβ_1-42 and the postsynaptic maker PSD95 particularly in the early stage, distinct regional distributions of Aβ_1-42 and N-terminally truncated Aβ42 (Aβ_t-42), and a significant association between Aβ_t-42 and tau in AD. Moreover, this study observed that Aβ_1-42 was associated with other synaptic proteins, but not neurofilament proteins. Notably, several proteases, particularly cathepsin B, cathepsin D and DPPIV, exhibited strong regional correlations with total Aβ_x-42, Aβ_t-42, Aβ_x-40, and tau accumulations in AD, forming coordinated regional distribution patterns. Such strong regional associations with late-stage Aβ species and tau were not observed for neuroglial markers. At the microscopic level, these proteases displayed abnormal morphologies proximity to Aβ and tau pathologies. Their coordinated regional distributions with Aβ_t-42, Aβ_x-40, and tau may indicate that these proteases cooperatively promote neurodegenerative cascades in AD.

This study explores the cell fate reprogrammability of H3K27M-mutant pediatric high-grade gliomas (pHGG) using neuronal transdifferentiation as a potential targeted therapy. We treated the BT245 patient-derived glioma cell line with pharmacological combinations targeting neuronal differentiation pathways and performed bulk RNA sequencing to characterize gene expression patterns driving cell fate transitions. Our findings reveal that the drug combinations induce transcriptomic changes consistent with differentiation towards neuronal phenotypes, including the upregulation of synaptic and dendritic signaling genes and the downregulation of malignant signatures. In comparison, astrocytic differentiation media (DM) and H3K27M knockout (KO) promote residual astrocytic phenotypes, suggesting neuronal transdifferentiation as a more effective strategy for mitigating tumor aggressiveness and progression. Differentially expressed genes such as GRIK1, GRIN1, NRXN3, NRXN1, CALB2, SCGN, SLC32A1, SLC1A2, KCNC3, and neurodevelopmental regulators including WNT7A, DLX6, ERBB4, ARX, BCL11B, SEMA3C, and FGFBP3 were identified as key markers regulating the neuron-like lineage transition. This study demonstrates that pHGGs can be phenotypically redirected toward neuronal-like identities through modulating cell fate differentiation programs. These findings advance the concept of 'differentiation therapy' as a promising intervention to reduce phenotypic plasticity and malignancy in pHGG ecosystems. While these are early in vitro findings, the potential ability to steer and control glioma cells toward stable, less malignant fates offers promising translational potential for patient-centered targeted therapies.

Meningiomas are common intracranial tumors with complex behavior that can be difficult to predict. Historically, morphology has been used to predict tumor aggressiveness and risk of recurrence, but this strategy has limitations as a prognostic tool. DNA methylation, transcriptomics, and copy number data are valuable for identifying groups of tumors with distinct biological signatures, thereby predicting recurrence risk. Multiple risk-stratifying classifiers which incorporate methylation data are available, but to date, a clinically validated risk-predicting classifier which exclusively uses methylation data has not been created. Using samples from 217 patients, we developed, validated, and implemented a clinically applicable methylation classifier for prognostic stratification of meningiomas based on k-means clustering of methylation data. Our classifier is 96% accurate, with 91% of samples receiving high confidence scores in the validation cohort (n = 76). This classifier is unique in that it includes de novo identification of risk groups by DNA methylation, confidence score calculation, internal clinical validation, and public model availability. Our newly validated classifier has the potential to aid diagnostic workup, improve recurrence risk prediction, and enhance clinical management of meningiomas.

Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons-cells that normally express only 3R-tau-induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.