Acta Neuropathologica最新文献

Our recent work on the prion protein and Na⁺, K⁺-ATPases (NKAs) led us to revisit data from over 50 years ago, which suggested similarities between vacuolation phenotypes in rodents poisoned with cardiac glycosides (CGs) and spongiform degeneration in prion disease. At that time, this hypothesis was dismissed because the vacuolation observed in prion diseases affects neurons, whereas CG poisoning in rodent brains led to swellings of the endoplasmic reticulum (ER) in astrocytes. We speculated that this difference might be specific to rodents and document here that the vacuolation shifts to neurons in mice expressing a humanized NKA α1 subunit. Next, we investigated the molecular mechanisms that could cause similar ER vacuolation in human cells in vitro. We found that certain stressors—such as overexpression of NKA α subunits and exposure to specific toxins known to trigger the unfolded protein response—can induce a phenotype characterized by profound ER dilation that is most strikingly observed for the perinuclear space (PNS). The ion imbalance typically caused by functional NKAs does not contribute to this phenotype. In fact, it can occur even with the overexpression of catalytically inactive NKAs. Several lines of evidence, generated with pharmacological agents, ion-specific dyes, antagonists, and truncated expression constructs, suggest that a calcium leak channel in the ER, known as transient receptor potential vanilloid 2 (TRPV2), plays a role in this ER and PNS dilation. Additionally, we observed that the formation of these vacuoles coincides with a decrease in steady-state levels of the lipid kinase PIKFYVE, which is recognized for its role in endolysosomal fission and fusion processes. Finally, we found evidence of vacuoles in cryosectioned brains of prion-infected mice that can be filled with a fluorescent marker targeted at the ER and PNS. This raises the possibility that this vacuolation phenomenon contributes to spongiform degeneration seen in prion diseases.

The identification of biomarkers predicting the burden of brain alpha-synuclein (α-syn) pathology in vivo represents a research priority in Lewy body disease (LBD). Recently, some kinetic parameters of seed amplification assays (SAAs) for α-syn showed associations with measures of clinical progression. However, preanalytical and analytical factors significantly affect these parameters, reducing reproducibility. The Endpoint Dilution (ED) SAA Real-time Quaking-induced Conversion (RT-QuIC) is emerging as an alternative, more accurate tool for seed quantification. Still, the approach needs validation in large patient cohorts. We applied the ED RT-QuIC to postmortem ventricular cerebrospinal fluid (CSF) samples from 357 brain donors, including 168 who showed LBD at neuropathologic examination. We estimated the seeding dose, yielding positive responses in 50% of replicate reactions (SD50), using the midSIN algorithm and correlated these values with postmortem synuclein pathology burden and clinical severity measures. LBD was staged through the Unified Staging System for Lewy Body Disorders and the Lewy pathology consensus criteria. The SD50 values (expressed in log₁₀SD/ml) differed significantly among participants at different LBD stages (p < 0.0001), with those at a neocortical stage demonstrating higher values than those at a brainstem-predominant stage (p < 0.0001). The SD50 values were significantly associated with the LBD load evaluated through immunohistochemistry (Rho = 0.62, p < 0.0001). Participants showing higher SD50 values performed worse at the last available scores on clinical scales evaluating motor (Rho = 0.33, p < 0.0001) and olfactory functions (Rho = − 0.33, p < 0.0001). The SD50 scores accurately distinguished neocortical LBD participants from those at lower stages (area under the curve, 0.86; 95% confidence interval, 0.79–0.92). The CSF ED RT-QuIC measure of α-syn seeds correlated significantly with LBD burden and clinical severity scores. These findings validate the CSF ED RT-QuIC as a quantitative assay for misfolded brain α-syn in LBD. This novel approach may be clinically applied to identify individuals at different stages of LBD pathology in research settings.

Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g., EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OE’s middle stratum and in the OB’s olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Targeted treatments (ZnSO₄ and AAVs) were applied at the OE level to assess the impact on tau pathology in the CNS. Complete stripping of the OE by intranasal administration of ZnSO₄ led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human postmortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to aging or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.

Patients with autoimmune inflammatory demyelinating diseases have been shown to present with trigeminal and cochlear nerve lesions restricted at the root transition zone, which contrasts with the relatively extensive distribution of lesions in optic neuritis. To better understand the mechanism underlying the different distribution pattern for cranial nerve lesions in these autoimmune neuroinflammatory diseases, we focused on the CNS–PNS transition zone (TZ) of the trigeminal and cochlear nerves in a MOG-driven active EAE model. These nerves were found to exhibit unique arrangements of anatomical barrier layers including the arachnoid and glia limitans, which affected cerebrospinal fluid (CSF) tracer distribution as well as CCR2⁺ immune cell infiltration. Our data demonstrated that CCR2⁺ immune cells accumulate at the TZ on both CNS side and PNS side of the trigeminal nerve and cochlear nerve, which mirror the locations of cranial nerve pathology observed clinically in patients with inflammatory demyelinating disease. On the other hand, the optic and olfactory nerves, which both lack a TZ, did not exhibit restrictions in immune cell localization. Overall, our results reconcile with the hypothesis that the segment of the cranial nerve that is exposed to CSF flow is more susceptible to CCR2⁺ immune cell infiltration.

The mutation E200K in the prion protein gene (PRNP) is the most common variant in genetic Creutzfeldt–Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesis that the prion strains responsible for this form of the disease may be related to those involved in sporadic CJD (sCJD). In this study, we characterized the prion strains responsible for E200K gCJD cases from Slovakia (n = 12), Spain (n = 9), and France (n = 3) using transgenic mouse models expressing human prion protein (PrP). The cohort included patients with various PRNP genotypes: E200K-Met₁₂₉/Met₁₂₉, E200K-Met₁₂₉/E200K-Met₁₂₉, E200K-Met₁₂₉/Val₁₂₉, and E200K-Val₁₂₉/Val₁₂₉. Prion strain characterization revealed that the strains isolated from E200K gCJD cases corresponded to the two most common strains identified in sCJD cases: M1^CJD and V2^CJD. Depending on the individual, these strains were either present as pure M1^CJD or V2^CJD, or as a mixture of both (M1^CJD + V2^CJD). Additionally, peripheral tissues from E200K-Met₁₂₉/Met₁₂₉ patients (n = 4) and one E200K-Met₁₂₉/Val₁₂₉ case were analyzed for prion infectivity and seeding activity. Similar to sCJD patients, low but detectable levels of prions were found in various peripheral tissues of E200K gCJD cases. Overall, our findings suggest that the prion strains and their distribution in the body are highly similar between E200K gCJD and sCJD patients. These similarities indicate that individuals carrying the E200K mutation may serve as a valuable model for understanding CJD pathogenesis during the preclinical phase of the disease.

Bacterial infections of the central nervous system (CNS) pose a significant threat to public health, especially with the growing challenge of antimicrobial resistance. Among these, Listeria monocytogenes (Lm) stands out as a key pathogen, responsible for often fatal neurolisteriosis in humans and cattle. Emerging evidence highlights the distinct roles played by microglia, the resident macrophages of the CNS, and infiltrating monocyte-derived macrophages (MDM) during neuroinflammation. Using bovine models, we investigated the interactions between these two macrophage populations and Lm during infection. Our results show that Lm thrives in the cytosol of microglia, driving productive infection and facilitating bacterial spread. In contrast, MDM effectively sequesters Lm within the phagolysosomal system, limiting its replication and inducing a viable but non-culturable (VBNC) state without completely eliminating the pathogen. Listeriolysin O contributes to the dichotomy of Lm fate, determining whether Lm escapes into the cytosol or transitions to the VBNC state. These findings underscore the complexity of Lm-host dynamics in neurolisteriosis, emphasizing the distinct yet complementary roles of microglia and MDM in shaping CNS infection. By elucidating these mechanisms, our study offers new perspectives on the neurolisteriosis pathogenesis and opens avenues for innovative therapeutic approaches to combat bacterial neuroinfections.

Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). Currently, the risk of progression is evaluated using atypical features and an elevated Ki67 proliferation index. However, these markers lack consistent definitions, raising the need for objective criteria. Genome-wide DNA methylation profiles were examined in 136 tumors histologically classified as CN. Clinical/histopathological characteristics were assessed in 93/90 cases, and whole-exome sequencing was conducted in 12 cases. Clinical and molecular characteristics were integrated into a survival model to predict progression-free survival (PFS). A diagnosis of CN was epigenetically confirmed in 125 of 136 cases (92%). No DNA methylation subgroups were identified, but global DNA hypomethylation emerged as a hallmark feature of CN associated with higher recurrence risk. Risk stratification based on histological features of atypia and Ki67 proliferation index was not reproducible across neuropathologists. Hypomethylation at the FGFR3 locus, accompanied by increased FGFR3 protein expression, was observed in 97% of cases. Gross total resection was associated with significantly improved PFS compared to STR, while patients undergoing STR receiving radiotherapy had a better outcome (p = 0.0001). Younger patients were identified as having a higher risk of recurrence (p = 0.026). Patient age and treatment strategy were key factors associated with survival outcomes in this cohort. These findings underscore the importance of closer follow-up for younger patients and radiotherapy for STR cases. Furthermore, FGFR3 represents a hallmark feature and potential therapeutic target, warranting further investigation.