Acta Neuropathologica Communications最新文献

Transgenic mice overexpressing bank vole prion protein with the isoleucine 109 polymorphism, TgVole(I109)4x, develop spontaneous neurodegenerative disease with sex-dependent onset, averaging 170 days in females and 200 days in males at terminal stage. The clinical and pathological features closely resemble Gerstmann-Sträussler-Scheinker syndrome (GSS), with characteristic ataxia, dysmetria, kyphosis, and prominent PrP plaques. Biochemical analysis reveals an atypical prion protein banding pattern with a distinctive low molecular weight band (7-10 kDa) following proteinase K digestion, similar to other atypical prion diseases such as small ruminants atypical scrapie (AS). Importantly, these spontaneously generated prions are highly infectious when passaged to mice expressing the same I109 polymorphism as well as to wild bank voles carrying the I109 polymorphism, but not to models expressing the methionine variant at this position, demonstrating the critical role of this specific polymorphism in atypical prion propagation. Temporal analysis reveals that infectious prions emerge significantly (2-3 months) before clinical signs appear, offering important insights into the pre-clinical phase of prion diseases. Serum neurofilament light chain levels increase significantly at 80 days of age, approximately 100 days before clinical onset, providing a wide therapeutic window with a reliable biomarker. The TgVole(I109)4× model exhibits extraordinary versatility in propagating diverse prion strains, showing remarkable susceptibility to atypical prions (including GSS and AS) with exceptionally short incubation periods, while maintaining the ability to efficiently propagate classical and recombinant prion strains. We present here a thoroughly characterized transgenic mouse model that spontaneously develops an atypical, bona fide prion disease with sex-related differences in disease onset. This model offers valuable insights into spontaneous and atypical prionopathies while demonstrating exceptional versatility for studying diverse prion strains and potential utility for evaluating therapeutic interventions when used with appropriate study designs that account for individual variability.

Schizophrenia (SZ) is epidemiologically linked to an increased risk of developing age-related dementias (ARD) predominantly characterized by Alzheimer's disease and vascular dementia. However, the molecular mechanisms underlying this association remain insufficiently elucidated. Extracellular vesicles (EVs) play a critical role in neuropathological processes and offer a promising avenue for identifying shared disease mechanisms and potential circulating markers for patient stratification. Here we used a two-phase systems biology approach integrating discovery-driven proteomics with a targeted validation strategy using data-independent acquisition mass spectrometry (DIA-MS) in a large, independent SZ cohort. First, we analyzed brain-derived EVs (bEVs) from post-mortem SZ and ARD subjects to identify shared molecular signatures. Next, we validated the presence and circulation of these bEV markers in circulating plasma EVs (pEVs) using DIA-MS data. Remarkably, SZ and ARD bEV proteome and peptidome showed overlapping alterations in neuronal connectivity, synaptic integrity, neuroinflammation, and metabolism. Unsupervised clustering analysis of correlated bEV/pEV markers stratified SZ patients into two clusters: high dementia risk and control-like profiles. Collectively, these data emphasize the significance of bEVs as crucial mediators of shared neuropathogenic mechanisms in SZ, and ARD. Furthermore, we identified a set of pEVs markers, including proteins and specific peptides, with a robust and promising bench-to-bedside trajectory that may facilitate the stratification of SZ patients at risk for ARD.

Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2B^In5 and CHMP2B^Δ10. Here, we found that wildtype CHMP2B (CHMP2B^WT) is mostly present in the cytoplasm, but CHMP2B^In5 is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2B^WT and ALS-associated CHMP2B^Q206H, and its loss in CHMP2B^In5 is responsible for the observed nuclear mislocalization. CHMP2B^Δ10 remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2B^In5 in FTD3 pathogenesis.

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder often preceded by an initial precipitating event, followed by a latent phase, and culminating in chronic epilepsy with recurrent seizures. The molecular and cellular mechanisms driving this transformation remain incompletely understood. Here, we applied Visium-based spatial transcriptomics to coronal brain sections from lithium-pilocarpine-induced status epilepticus (SE) rats and controls (n = 16) to map transcriptional dynamics across epileptogenesis. Spatial clustering accurately defined anatomically relevant regions and canonical markers in controls. Comparative analyses revealed extensive SE-associated transcriptional alterations spanning latent and chronic phases across all examined regions. Notably, spatial profiling demonstrated that microglial activation and reactive astrogliosis extended well beyond the hippocampus, encompassing white matter tracts and multiple thalamic nuclei during the latent phase. Cell-type deconvolution further identified pronounced regional shifts in astrocyte functional subtypes within these reactive zones. These findings uncover the spatial heterogeneity of epileptogenic processes, highlighting previously underappreciated thalamic and white matter involvement. The identification of region-specific glial responses and astrocyte subtype transitions provides new mechanistic insights into epileptogenesis and underscores the need for region- and cell-type-targeted strategies to inform therapeutic interventions in TLE.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease characterized by the presence of abnormally phosphorylated tau aggregates. Tau is a microtubule-associated protein expressed mainly in axons of neurons with a role in the regulation of microtubule dynamics and axonal transport. It is totally unknown when and how tau is abnormally hyperphosphorylated in CTE brains. Unlike other tauopathies such as Alzheimer's disease, in which diseases start several decades before clinical symptoms and the time point of onset is not clear, in the case of CTE it is evident when and what impacts are given to cause the diseases. Repetitive mild traumatic brain injury (rmTBI) is a known causative factor for CTE, particularly in athletes engaged in contact sports, individuals involved in traffic accidents, and military personnel exposed to blast injuries. We hypothesized rmTBI to be a useful experimental paradigm for investigating the initial processes of tau hyperphosphorylation in CTE. Among the various experimental models for TBI reported to date, we focus on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), because it appears to replicate human TBI more faithfully than other models particularly regarding on the impact mechanism and pathology. After verifying that CHIMERA rmTBI induced brain injuries analogous to human CTE, we investigated tau pathology in wild-type (WT) and P301S human tau transgenic (Tg) mice subjected to CHIMERA rmTBI. While no hyperphosphorylated tau signal was observed in any region of the WT mouse brain, an increased number of AT8-positive cells were detected in the motor and sensory cortices of P301S Tg mouse brains, accompanied by dendritic abnormalities, after rmTBI. Further, we found that CHIMERA rmTBI enhanced the spreading of tau pathology in brains of WT mice when tau fibrils were inoculated. These results suggest a possibility that rmTBI constitutes a risk factor stimulating the progression and propagation of tau pathology, rather than causing the initial events, if tau aggregates are present in the brain and that CHIMERA rmTBI may serve as a valuable experimental model for investigating its molecular mechanisms.

Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) are slow- or non-progressing epileptogenic tumors, typically occurring in young adults. These tumors are highly calcified and exhibit both diffuse growth and oligodendroglioma-like patterns. Epithelioid glioblastomas (E-GB) are rare and aggressive variants of isocitrate dehydrogenase wildtype glioblastomas (GB), associated with poor overall survival. Both PLNTY and E-GB often carry oncogenic BRAF V600E mutation (BRAF_V600E). In this case study, we analyzed clinical and genetic data from a single patient who, based on extensive histological and molecular evaluation, was diagnosed to carry PLNTY-like tumor that progressed into E-GB years later. The aim of our study was to uncover the genetic drivers and the evolutionary history of these tumors. Progression of the PLNTY-like tumor into E-GB was investigated using histology, chromosomal karyotyping, whole-genome sequencing (WGS), and RNA sequencing. A typical immunohistochemical stain pattern of CD34 positivity was detected in the apparent PLNTY, whereas it was depleted in the E-GB sample, as expected. WGS analysis of the PLNTY and three E-GB samples revealed four genes with shared somatic protein-altering mutations: BRAF (carrying BRAF_V600E), clonal in both PLNTY and E-GB, as well as GNS, FOXRED2, and SSTR5, which were subclonal in PLNTY and clonal in E-GB. Both the PLNTY-like and E-GB tumors also carried highly similar copy number alteration profiles with a prominent loss of heterozygosity (LOH) in the majority of the chromosomes, suggesting their monoclonal origin. PLNTY-like tumor was mainly diploid, and the tumor underwent a genome-wide duplication event during the progression to E-GB. Furthermore, two focal rearrangements leading to homozygous deletion of CDKN2A/B were detected in E-GB samples. In conclusion, this study revealed unusually extensive LOH in the histologically and genetically supported PLNTY-like tumor that progressed into E-GB. Notably, only a limited set of genetic alterations was associated with malignant transformation beyond genome duplication, the CDKN2A/B inactivation representing the best-known oncogenic driver for malignant transformation. These findings suggest that genomic profiling may be a valuable tool for the diagnosis and prognostic assessment of low-grade neuroepithelial lesions.

Damage to long myelinated axons of white matter tracts is a hallmark pathology resulting from traumatic brain injury (TBI) forces and secondary injury processes. 4-aminopyridine (4-AP) is an FDA-approved Kv1 potassium channel inhibitor designed to mitigate axon dysfunction. We examined repurposing 4-AP as an acute TBI treatment using clinically-oriented neuropathology of axon damage combined with unbiased genome-wide spatial transcriptomics for comprehensive analysis of secondary injury processes. Adult male and female mice received a non-penetrating impact TBI with 4-AP (i.p., b.i.d) on days 1-7 post-injury. Along corpus callosum (CC) axons, TBI disrupted node of Ranvier domains, exposing the putative 4-AP target of mislocalized Kv1 channels (p < 0.005). Clinically reasonable 4-AP dosing (0.5 mg/kg) reduced nodal Nav1.6 channel loss (p < 0.05) and Caspr heminode formation (p < 0.005) after injury. Quantification of β-amyloid precursor protein immunolabeling showed significantly reduced CC axon damage at 4-AP doses of 0.5 mg/kg and 5 mg/kg (each p < 0.005). 4-AP safety, based on potential seizure risk after TBI, was unaltered with vehicle or 0.5 mg/kg 4-AP, while the 5 mg/kg dose induced seizure behavior in sham and TBI groups (p < 0.0001). Spatial transcriptomics mapped molecular signatures to tissue pathology. TBI increased axonal injury response genes in the CC and in motor and somatosensory cortex sites of CC projection neurons. TBI induced disease-associated glial phenotypes that mapped predominantly within the CC. TBI increased pathway expression for immune and vascular functions, neuron and glial cell signaling, and cellular dyshomeostasis, while reducing expression in myelination-related pathways. Gene expression analysis of 4-AP treatment (0.5 mg/kg) indicated potassium channel target engagement and increased neuroaxonal activity, along with dampened secondary injury responses. Collectively, these findings reveal underlying molecular pathology of the secondary injury response and advance 4-AP translation to reduce axon damage and stimulate activity-dependent repair after acute TBI.

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.