Brain Pathology最新文献

The 14-3-3 protein family plays a crucial role in cellular signaling and neuronal survival. Although 14-3-3 isoforms have been involved in the etiology of some neurodegenerative disorders, their role remains poorly understood in alpha-synucleinopathies. In this study, we wanted to characterize 14-3-3 gene expression patterns in the brain and periphery of patients with Lewy body pathology (LBP). We analyzed messenger RNA (mRNA) expression of all seven 14-3-3 isotypes in the temporal cortex and caudate nucleus of brains with pure and common LBP, as well as in cerebrospinal fluid, peripheral blood, and platelets. Stratifin (SFN) protein expression was assessed by immunohistochemistry and enzyme-linked immunosorbent assay. Effects of SFN overexpression on astrocyte activation were investigated in vitro. In the temporal cortex of LBP patients, six out of seven 14-3-3 genes were significantly downregulated, while SFN was markedly up-regulated. SFN protein localized to neurofibrillary tangles in the parahippocampal region and reactive astrocytes in white matter. In vitro, SFN treatment induced biphasic changes in astrocytic glial fibrillary acidic protein expression, suggesting a role in glial activation. Peripheral analysis revealed no significant 14-3-3 mRNA changes in blood, but platelet expression patterns inversely correlated with brain tissue; six isoforms were up-regulated, and SFN was strongly downregulated in dementia with Lewy bodies (DLB) platelets. Our findings revealed an important shift in 14-3-3 isotype expression in the temporal cortex of LBP patients, where SFN up-regulation reflected its colocalization with tau pathology and astrocytic reactivity. The inverse expression profile in platelets in DLB highlights their potential as accessible biomarkers for molecular changes occurring in the brain.

Alzheimer's disease (AD) may display various clinical phenotypes with different disease progressions, such as rapidly progressive Alzheimer's disease (rpAD) type. The reason for clinical heterogeneity is still unknown and not predictable. Here, we subjected frontal cortex-derived tau seeds from classical AD, rpAD patients and controls to tau real-time quaking-induced conversion (RT-QuIC) assay analysis and examined biochemical properties, toxicity, and the morphology of tau fibrils generated during the RT-QuIC applying a cell-based assay and transmission electron microscopy (TEM). We observed seeding activity of misfolded tau protein in AD patients, which was significantly higher than in control cases. Additionally, the RT-QuIC signal response revealed differences between AD cases with a classical clinical phenotype and those with a rapidly progressive course of the disease (rpAD). The RT-QuIC reaction seeded with brain from rpAD exhibited a shorter lag phase, higher area under the curve and a higher seeding end point dilution compared to classical AD, independent from the Braak stage. The cellular toxicity of thioflavin T-positive RT-QuIC products from rpAD-seeded reactions was higher compared to those seeded by classical AD and controls. Morphological characterization of brain tissue-seeded RT-QuIC end-products via TEM showed that tau fibrils derived from rpAD seeded reactions revealed subtly different morphologies compared to classical AD. The study provides evidence for the existence of different tau assemblies in AD with different progression rates. As an alternative explanation, differences in the amounts of misfolded seed or the presence of other co-factors might influence the seeding activity of tau in AD and rpAD patients.

A novel class of active immunotherapy, consisting of proprietary T-helper peptide linked to a B-cell epitope, is being developed to target tau in Alzheimer's disease (AD). These experimental therapies generate antibodies that have demonstrated binding to pathological tau in vitro, and efficacy in cell-based tau aggregation assays comparable to monoclonal antibodies. Here, we report the ability of one such tau-targeting immunotherapy, p5555kb, to prevent the progression of tau pathology using two distinct mouse models. P301L mice were immunized with p5555kb and showed greater survival rates at 210 days than saline-inoculated control mice. The efficacy of p5555kb against tau seeding in vivo was assessed by injecting C57BL6 mice with tau fibrils purified from post-mortem human AD brain tissue. Immunization with p5555kb significantly reduced the amount of tau inclusions detected by immunohistochemistry at 9 months post-injection, as compared to saline inoculation. This study demonstrates that p5555kb is effective at inducing functional tau-targeting antibodies, which prevented the onset of adverse phenotypes associated with tau pathology in vitro and in vivo.

There is a paucity of autopsy-based studies providing detailed neuropathological characteristics of fatal hypothermia cases, particularly in trauma-associated cases. Hence, this study investigated 2054 serial autopsy cases in which histopathological examination of all organs, including the brain, could be performed. We identified 168 cases (75 female and 93 male patients) of fatal hypothermia and examined the clinical and neuropathological characteristics in these cases. Patients aged ≥65 years constituted 80% of the cohort (135 cases). Cognitive impairment (CI) was identified in 39% of cases with available clinical histories, and approximately half of these cases were presumed to have developed hypothermia while wandering, based on clinical history and the circumstances of discovery. Alzheimer's disease was the most commonly identified pathology, affecting 40% of the total and approximately two-thirds of patients aged ≥80 years. CI caused by multiple pathologies, especially two, was more frequently observed than by a single pathology. The most common manner of exposure to cold temperatures was accidents (120 cases), including 35 cases with multiple traumatic injuries, most likely resulting from falls. In these cases, the trauma was considered the primary cause of immobility, leading to subsequent exposure to cold environments. Importantly, 30 (86%) of these trauma-associated cases showed one or more neuropathological conditions, and CI was documented in 13, with four presumed to have fallen while wandering. Notable neuropathological manifestations were also observed in eight of the 33 cases of patients aged less than 65 years. Our results demonstrate that neurodegenerative diseases, especially Alzheimer's disease, are underlying conditions in fatal hypothermia in the elderly and in relatively younger individuals, suggesting that they may contribute to its onset. These findings highlight the necessity for comprehensive neuropathological examination in all forensic autopsy cases of hypothermia.

Vessel-associated microglia (VAM) are an integral part of the neurovascular unit and have recently been implicated in the pathophysiology of cerebrovascular injury and blood-brain barrier (BBB) leakiness in Alzheimer's disease (AD). In this neuropathological study, we explored the hypothesis that the distribution and activation of VAM are altered in AD in the presence of systemic infection, associated with cerebrovascular dysfunction. We studied VAM density in the temporal cortex and underlying white matter from AD and age-matched controls with and without terminal systemic infection (SI) (n = 15 per group). The area of VAM labelled with microglial markers (Iba1, HLA-DR, CD68) was quantified in proximity to CD31-labelled microvessels within three predefined regions: contact VAM, proximity <15 μm, and parenchymal >15 μm. The relationships between VAM and previously measured brain cytokine levels and biochemical markers of cerebral perfusion (MAG:PLP1, endothelin-1) and BBB leakiness (VEGF-A and fibrinogen), were explored in a subset of cases. Compared to controls, the relative area of Iba1+ VAM was higher in SI and in AD. The area of HLA-DR+ VAM was higher in AD only. The area of Iba1+ VAM that expressed CD68, a marker of phagocytosis, was higher in both AD and AD + SI. Iba1+ and HLA-DR+ VAM correlated inversely with anti-inflammatory cytokines (IL-10, IL-23) in AD and positively with pro-inflammatory cytokines (IL-6, IL-23, GM-CSF, IL-17) in AD + SI. Iba1+ VAM density correlated positively with endothelin-1, VEGF-A and fibrinogen in controls. HLA-DR+ VAM density correlated positively with Aβ_1-42 in both controls and AD, and inversely with PDGFRβ and VCAM-1 in AD. Our data reveal the distribution of VAM is elevated in AD, and altered in the presence of systemic infection, which together are likely to be independent and synergistic contributors to cerebrovascular dysfunction in AD.

Byman E, Schultz N, Netherlands Brain Bank, Fex M, Wennström M. Brain alpha-amylase: a novel energy regulator important in Alzheimer disease? Brain Pathology.2018;28: 920–932. https://doi.org/10.1111/bpa.12597

In this article, the incorrect version of image H in Figure 1 was published. The image depicts amylase staining of a pericyte/vessel. Certain red areas adjacent to the pericyte and vessel had been removed. This altered image was accidentally included in the publication.

This correction does not affect the results, interpretations, or conclusions of the study, as the main findings concern neurons rather than pericytes.

We apologize for this error.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and the presence of TAR DNA-binding protein 43 (TDP-43) aggregation in the brain. Dyslipidemia is a common feature of ALS, and increasing evidence indicates that lipid dysregulation in the central nervous system underlies ALS pathology. Sphingomyelin is a sphingolipid that is highly enriched in the human brain. However, very little is known about changes in sphingomyelin in the context of ALS brain. We therefore undertook a comprehensive analysis of sphingomyelin in the disease-affected motor cortex and disease-unaffected cerebellum in sporadic ALS with TDP-43 pathology using liquid chromatography-mass spectrometry. We found that sphingomyelin was significantly increased in the ALS motor cortex compared to controls and was strongly associated with disease duration. In contrast, sphingomyelin was unaltered in the cerebellum. The increase in sphingomyelin was associated with an upregulation of ATP-binding cassette subfamily A member 8 (ABCA8), a sphingomyelin transporter, only in the motor cortex of ALS. Importantly, both sphingomyelin and ABCA8 were associated with TDP-43 only in the motor cortex. These results suggest that increases in sphingomyelin and ABCA8 could be a protective response against TDP-43 pathology.

The meninges, which originate from the neural crest cells and mesoderm, play crucial roles in the formation, protection, and homeostasis of the central nervous system. Meningiomas, which arise from the meninges, are the most common primary intracranial tumors, and their recurrence and malignant transformation represent major clinical challenges. Recent studies have identified mesenchymal stromal cell- and fibroblast-expressing Linx paralogue (Meflin), as being expressed in the meninges, but its role in meningeal development and meningioma pathophysiology remains poorly understood. In this study, we investigated the expression patterns of Meflin during meningeal development and in meningioma tissues. Meflin expression was detected in the head of a Meflin reporter mouse line at approximately 11.5 days of embryonic life, suggesting its involvement in early meningeal development. Lineage-tracing experiments revealed that Meflin mRNA⁺ cells contribute to the postnatal formation and turnover of meningeal cells in adulthood, indicating their role in meningeal homeostasis. In human meningioma samples, Meflin expression was observed in normal meningeal cells and almost all tumor samples, with higher expression levels correlating with higher histological grades and increased recurrence rates. Analysis of a publicly available meningioma gene expression dataset revealed that tumors with high Meflin expression exhibited enhanced WNT ligand biogenesis and trafficking compared with tumors expressing low levels of Meflin. Furthermore, single-cell RNA sequencing analysis confirmed this finding and revealed elevated WNT6 expression specifically in clusters of Meflin-high tumor cells, highlighting a potential link between Meflin and WNT signaling activation in meningioma progression. Thus, this study provides novel insights into the role of Meflin in meningeal development and meningioma pathophysiology.