Acta Neuropathologica最新文献

Cerebral small vessel disease (cSVD) is a leading cause of stroke and vascular cognitive impairment, yet the cellular mechanisms underlying microvascular dysfunction in human disease remain incompletely understood. In particular, the relationship between pericyte alterations and endothelial activation, two key features of blood–brain barrier dysfunction, remains unresolved. Here, we performed a quantitative single-vessel analysis of the human cortical microvasculature across increasing cSVD severity and ageing. Using multiplex immunohistochemistry combined with spectral unmixing and automated image analysis, we analysed 11,409 microvascular fragments from post-mortem brain tissue derived from 20 cases. Endothelial cells, pericytes, and endothelial activation were assessed using PECAM-1, PDGFRβ, and VCAM-1, respectively. Microvascular density and diameter differed between cortical grey matter and the underlying white matter, with white matter vessels being less dense and wider in controls. While vessel diameter remained stable across cSVD severity groups, microvascular density increased with cSVD severity and age in the white matter. At the molecular level, PDGFRβ signal decreased markedly with increasing cSVD severity, consistent with reduced pericyte coverage. This reduction was observed in both grey and white matter and correlated with disease severity and age. Notably, intermediate severity groups displayed marked heterogeneity, with vessels exhibiting either preserved or markedly reduced PDGFRβ signal. In parallel, endothelial markers PECAM-1 and VCAM-1 increased significantly with disease severity, reflecting endothelial activation. Unsupervised Gaussian mixture clustering of marker expression identified three vascular states characterised by (i) preserved PDGFRβ signal with low endothelial activation, (ii) reduced PDGFRβ signal without endothelial activation, and (iii) reduced PDGFRβ signal combined with endothelial activation. These clusters broadly aligned with neuropathological severity but revealed heterogeneity not captured by post-mortem diagnosis alone. Together, these findings suggest that pericyte alterations and endothelial activation are partially dissociated processes in human cSVD and identify distinct microvascular phenotypes across disease severity. These cross-sectional observations provide a framework for future longitudinal and experimental studies to determine their temporal and mechanistic relationships.

Posterior Fossa A (PFA) is the most frequent and clinically aggressive ependymoma (EPN) subgroup, with relapse typically representing a terminal event despite intensive multimodal therapy. Ultra-high-risk PFA EPNs are characterised by chromosome 6q loss (6q-) with or without chromosome 1q gain (1q +). While the molecular mechanisms driving 1q+ have been elucidated, 6q- PFA pathobiology remains poorly understood. Here, we show that loss of 6q in PFA EPN results in deletion of LATS1 (Large Tumour Suppressor Kinase 1), thereby dysregulating the Hippo signalling pathway and enhancing YAP/TEAD activity. Integrated analyses of primary and recurrent PFA EPNs, incorporating clinical, multiomic, and functional assays, were performed to define the biology and therapeutic susceptibility of 6q- PFA EPNs. Cumulative 6q loss was associated with nearly half of PFA EPN-related deaths. Copy number profiling identified the LATS1 locus as recurrently deleted across all 6q- cases, including 10/60 with partial 6q deletions. Restoration of LATS1 expression in 6q- PFA cell lines re-established protein levels and suppressed proliferation. Tumour analyses showed marked Hippo pathway disruption with elevated YAP expression and TEAD2-related transcriptional activity. TEAD2 palmitoylation inhibitor VT107, and Proteolysis Targeted Chimera (PROTAC) degrader H122, exhibited PFA 6q- selective activity in vitro. TEAD2 upregulation was further observed in a previously described undifferentiated, progenitor-like population of PFA EPN cells. In conclusion, 6q loss defines an aggressive biological subset of PFA associated with dismal outcomes. Identification of LATS1 as a recurrently lost tumour suppressor implicates Hippo pathway dysregulation as a central driver of malignancy, and we identify YAP/TEAD signalling as a potential therapeutic target.

Progressive supranuclear palsy (PSP) is an adult-onset neurodegenerative disease with a heterogeneous spectrum of clinical and pathological features. The epidemiology of PSP—as defined by the gold standard of autopsy diagnosis—remains unresolved, but prevalence estimates are typically ~1:10,000. Here, we analyzed the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set, aggregated from 38 U.S. Alzheimer’s Disease Research Centers (ADRCs). We compared clinical and neuropathologic features of autopsied participants, stratifying on cognitive status at recruitment into the cohort. The sample comprised 6845 individuals who were followed longitudinally for 4.0 (± 2.9 stdev) approximately yearly visits, n = 297 with eventual autopsy-verified PSP. Participants were not necessarily diagnosed or followed in movement disorder clinics. Among those with dementia or PSP at recruitment (n = 4310), 3.3% had corticobasal degeneration (CBD), 3.0% Pick’s disease, and 4.5% PSP pathology. Among those recruited while cognitively normal (n = 1451), 0.7% had CBD, and 0.1% Pick’s disease, while 3.2% had PSP pathology. This frequency of incident PSP pathology was higher than expected based on prior epidemiology studies. In comparing between incident (recruited normal) and prevalent (recruited with dementia or clinical PSP) cases with PSP pathology, those with incident PSP died older: 89.5 years vs 76.3 years on average. Furthermore, incident PSP pathology cases were less likely to manifest stereotypical PSP clinical features, but more likely to have parkinsonism. In a convenience sample of individuals with PSP pathology from the University of Kentucky ADRC (n = 23), digital pathology analyses using HALO software and AI-based analytic modules revealed that PSP tau pathology was more severe overall in prevalent PSP. Within the putamen, incident cases had a higher proportion of tufted astrocytes and lower proportion of NFTs. In conclusion, in this large multicenter sample, PSP pathology was more common than other FTLD-Tau subtypes, and incident PSP often differed clinically from “classic” PSP.

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), including the Parkinson’s disease (PD)-linked CHCHD2^T61I mutation, are associated with Lewy body disorders (LBDs) by unknown mechanisms. Here, we demonstrate that CHCHD2^T61I exacerbates age-related brain pathologies, including axonal degeneration and cognitive deficits, by disrupting the mitochondria-lysosome axis. Specifically, CHCHD2^T61I binds and reduces cathepsin B (CTSB) and cathepsin L (CTSL) levels, inducing lysosomal membrane permeability and impairing α-synuclein fibril clearance. We also demonstrate that human CHCHD2 declines in the brain with age, while expression of wild-type CHCHD2 safeguards against age-related neuroinflammation, dopaminergic neuron loss, insoluble protein aggregation, and structural deterioration of mitochondria and lysosomes. These findings, supported by observed reductions in CTSB and CHCHD2 in human LBD brains, establish CHCHD2 as a key regulator of neuronal resilience to aging and proteostatic collapse via the mitochondria-lysosome axis. Preventing age-associated CHCHD2 decline offers a therapeutic strategy to preserve brain health throughout aging.

The medial temporal lobe (MTL) is a key region in Alzheimer’s disease (AD) pathogenesis, affected early by tau pathology. While female sex and APOE-ε4 are two known risk factors that affect tau levels, whether these factors drive tau in the MTL via amyloid-dependent or amyloid-independent mechanisms remains unclear. We investigated these relationships in two large neuropathological cohorts comprising 2550 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP; n=1587, main cohort) and Arizona Study of Aging and Neurodegenerative Disorders (AZSAND; n=963, replication cohort) covering the whole AD continuum. Neuropathological assessments of global neocortical and regional MTL amyloid-β burden were used to determine the extent to which amyloid-β pathology mediated associations of APOE-ε4 carriership and sex with MTL tau burden. In both cohorts, APOE-ε4 carriership and female sex were associated with significantly greater MTL tau pathology (all p<0.001). Adjustment for global amyloid-β attenuated but did not eliminate these associations (p≤0.024). However, after jointly accounting for global and MTL amyloid-β burden, the association between APOE-ε4 and MTL tau was no longer significant in either cohort (p≥0.19), whereas the association between female sex and MTL tau remained robust (p≤0.004). Models incorporating both global and regional MTL amyloid-β explained substantially more variance in MTL tau burden than models including only global amyloid-β, and results were replicated when further adjusting for diagnostic group or neocortical tau burden. These findings suggest that APOE-ε4 and female sex influence MTL tau accumulation through partially distinct pathogenic pathways, supporting an additional contribution of regional amyloid-β to the APOE-ε4-associated MTL tau burden while implicating additional amyloid-independent mechanisms in female vulnerability to tau accumulation.

Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients, we show that stroke-associated pneumonia is associated with poor clinical outcome and long-term neutrophil deregulation. In mice exposed to transient middle cerebral artery occlusion (MCAO), experimental S. pneumoniae pneumonia induced at 3 days after stroke impaired neurological recovery and increased blood–brain barrier breakdown, brain neutrophil infiltrates, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Proteome analysis revealed that pneumonia induced a degranulation, platelet activation, and NETosis signature in peripheral blood neutrophils of MCAO mice, which was partly reversed by amoxicillin treatment. Subsequent studies showed that neutrophils were critical mediators of pneumonia-associated blood–brain barrier breakdown and microvascular thrombosis. Notably, administration of an antibody neutralizing extracellular histone proteins during pneumonia reduced ischemic injury, restored neurological recovery and prevented long-term brain atrophy in stroke-associated pneumonia mice. These protective effects were not observed after degradation of neutrophil extracellular traps by DNase-I, blockade of neutrophil extracellular trap formation by LDC7559 or myeloperoxidase inhibition by AZD4831, when these treatments were administered on occasion of pneumonia. This study identifies extracellular histones as key drivers of inflammatory brain injury and establishes histone neutralization as a strategy that protects against the deleterious effects of pneumonia after stroke.

The hallmark neuropathological feature of upper motor neuron (UMN) degeneration in amyotrophic lateral sclerosis (ALS) is the “sclerosis” of the lateral corticospinal tract (CST)—the major axonal pathway connecting UMNs to lower motor neurons (LMNs). However, few studies since Charcot’s original descriptions in the nineteenth century have directly correlated clinical UMN phenotypes with corresponding neuropathological findings. We examined the pathology of the lateral CST at the cervical, thoracic, and lumbar levels of the spinal cord from ALS patients with predominantly UMN (UMN-p) phenotypes and compared it with that in patients with predominantly LMN (LMN-p) phenotypes. We assessed myelin loss, axonal degeneration, neuroinflammation, and TDP-43 pathology. Spinal cords from UMN-p ALS cases exhibited pronounced myelin loss in the lateral CST compared to LMN-p cases and controls, consistent with clinical phenotyping. Quantitative analysis revealed significant axonal loss across all axon diameter ranges in UMN-p ALS, which was more severe than in LMN-p ALS. Importantly, axonal loss was more pronounced in the lumbar than in the cervical spinal cord. We identified a distinct population of foamy, inflammatory microglia localized to regions of severe myelin and axonal loss in UMN-p ALS. TDP-43 was measurably increased in the UMN axons of the lateral and ventral CSTs. In summary, “lateral sclerosis” of ALS correlates to clinically imputed UMN degeneration. It consists of a combination of myelin loss, distal greater than proximal axonal degeneration, inflammatory microglial activation within the CSTs, and abnormally increased axonal TDP-43. The length-dependent gradient of motor axonal loss supports a "dying-back" process. A detailed comparison of “dying-forward” and “dying-forward” is provided in the Discussion. The association of loss of axons and myelin with abnormal microglial activity shows glio-axonal interactions in UMN axon degeneration, the latter CST (lateral sclerosis) across all three spinal cord levels in the ALS UMN-p samples but does not establish a causal relationship.

TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein essential for RNA metabolism. Under physiological conditions, it predominantly resides in the nucleus but is also expressed in the cytoplasm, where it regulates mRNA trafficking and local translation. In nearly 97% of amyotrophic lateral sclerosis (ALS) cases, TDP-43 undergoes nuclear depletion and cytoplasmic aggregation. While its nuclear functions are well characterized, its axonal roles remain poorly understood, despite axonal degeneration being a hallmark of ALS pathology. To address this gap, we investigated TDP-43 localization and transport dynamics in axons of H9-derived human neurons. We compared fluorescently labeled TDP-43 with three well-characterized axonal cargoes, ras-related protein Rab5, synaptophysin, and amyloid precursor protein, and examined protein–protein interactions between TDP-43 and the axonal transport machinery. Our analyses revealed that TDP-43 exhibits active anterograde axonal transport and interacts with multiple kinesin motor proteins, including all three KIF5 isoforms, through the adaptor KLC1, and the synaptic vesicles motor KIF1A. This multi-motor engagement suggests a flexible transport system that ensures mRNA delivery to distal axons. In ALS, where TDP-43 accumulates abnormally in the cytoplasm, this flexibility may become compromised, with multiple transport mechanisms simultaneously affected. This could contribute to progressive accumulation of non-functional TDP-43 granules, disrupting mRNA trafficking and local translation. Our findings provide a foundation for understanding how physiological TDP-43 transport mechanisms may be impaired during disease, highlighting axonal TDP-43 transport pathways as potential therapeutic targets.