Journal of Neuropathology and Experimental Neurology最新文献

The aggregation of amyloid-β (Aβ) and phosphorylated tau (p-tau) in the human brain is associated with Alzheimer disease (AD). Although Aβ aggregation has been reported in various mammals, significant p-tau aggregation has been reported in only a few species. We examined Aβ and p-tau aggregation in the brains of 30 animals belonging to 12 artiodactyl species. Amyloid-β aggregates were observed in 2 animals (21 and 22 years old); p-tau aggregates were observed in all animals >9 years of age (n = 12). Regarding tau pathology, mildly affected animals exhibited neuropil threads (NTs), whereas severely affected animals exhibited NTs and neurofibrillary tangles. The most severe p-tau aggregation was observed in the parahippocampal gyrus, basal ganglia, hippocampus, and cerebral cortex. Proteinase K treatment resulted in high proteinase resistance for 4-repeat tau and low resistance for 3-repeat tau. These results suggest that p-tau aggregation occurs prior to Aβ aggregation in artiodactyls, which differs from other mammalian species and human AD. Regarding the distribution, p-tau aggregated in neurites and then in the neuronal cell soma of the parahippocampal gyrus and spread to associated regions of the brain. Moreover, 4-repeat tau was the main component of proteinase-resistant p-tau aggregates in the artiodactyl brains studied.

Cystatin C (CST3) colocalizes with amyloid-β (Aβ) around vessels in cerebral amyloid angiopathy (CAA). This study aimed to characterize CST3-Aβ interactions in CAA. Brain tissues from 12 Alzheimer disease (AD) and 5 non-AD control subjects, along with AD model mice (J20), were examined. In AD brains, immunohistochemistry revealed Aβ positivity around cortical and leptomeningeal vessels as well as in intra- and extracellular areas. Congo red-positive vessels were also present. Conversely, control brains showed only few Aβ-positive cells. CST3 was primarily intracellular in controls, but in AD, it was found both to be intracellular and perivascular, colocalizing with Aβ and Congo red in affected vessels. Vessel quantification showed a positive correlation between CST3-positive and Aβ- or Congo red-positive vessels. Moreover, most CST3-positive vessels were Cathepsin B (CatB)-negative. CatB was significantly decreased in AD and inversely correlated with CAA severity. Immunoprecipitation followed by Western blotting, dot blot, and TEM revealed oligomeric aggregates and short fibrillar CST3 bound to Aβ in both AD and J20 mice brains. In J20 mice, CST3 was only neuron-positive at 2 months, and vessel-positive, colocalizing with Aβ from 3 months. These findings suggest that aggregated CST3 binds to Aβ and accumulates around vessels, potentially contributing to CAA pathogenesis.

Theiler's murine encephalomyelitis virus (TMEV) infection in mice has been used to study diverse neurological diseases, including multiple sclerosis and epilepsy. In this investigation, 5 strains of collaborative cross (CC) mice were infected with TMEV and examined clinically and histologically at days 4, 14, and 90 post-infection (dpi). All CC strains tested exhibited lumbar spinal cord and/or ventral peripheral nerve lesions by 14 dpi; CC027, CC023, and CC078 strains exhibited lesions at 4 dpi. At 90 dpi, lesions were remnants of the inflammatory responses associated with earlier infection; there was skeletal muscle atrophy in the CC023 strain. Increased microglial/macrophage reactivity was observed in all strains at 4 and 14 dpi, but not at 90 dpi. TMEV mRNA expression was greatest in the CC023 and CC078 strains at the acute timepoints; TMEV was completely cleared in all mice at 90 dpi. The neuropathological and clinical profiles in CC023 mice, mainly at 14 dpi, share some clinical and histologic features with those in amyotrophic lateral sclerosis patients. This work demonstrates how viral infection might interact with the genetic background of a susceptible individual to contribute to the onset, clinical presentation and persistence of lesions despite viral clearance.

Mitochondria are critical for cellular function. Their dysfunction contributes to cell degeneration and death, leading to disease progression. This study examined mitochondrial changes in idiopathic inflammatory myopathies (IIMs) including antisynthetase syndrome (ASyS), dermatomyositis (DM), and inclusion body myositis (IBM). Skeletal muscle biopsies were analyzed using histology, histochemistry, and electron microscopy from patients diagnosed with IIMs, according to the clinico-sero-morphological classification. There was no significant age difference between 16 ASyS and 16 DM patients, but 11 IBM patients were significantly older. The ASyS group had higher serum creatine kinase levels and showed prominent mitochondrial abnormalities similar to IBM and greater than the DM group. While all IIM groups displayed conventional mitochondrial changes, including ultrastructural abnormalities with cristae alterations, paracrystalline inclusions were exclusive to IBM and ASyS. There were significantly more rod-like filamentous inclusions adjacent to mitochondria in the IBM and ASyS groups, compared to the DM group. Intra-mitochondrial filament aggregates with focal formation of inclusions were also identified in individual ASyS and IBM patients, suggesting a link between the mitochondrial filamentous inclusions and nuclear and/or cytoplasmic filamentous inclusions. These findings suggest that mitochondrial abnormalities, particularly in ASyS and IBM, may contribute to the pathogenic process and clinical manifestations of the disease.

We investigated the expression and distribution of 5 cytoadhesion receptors for the Plasmodium falciparum erythrocyte membrane protein 1 in 12 regions of post-mortem brains of 50 Malawian children, that is, 27 with the clinical and pathological diagnosis of cerebral malaria (CM) and 23 with a non-malarial cause of death. We quantified the expression of each receptor by microvascular endothelium and the colocalization of receptor-expressing microvessels with sequestered infected red blood cells (iRBC) and calculated a receptor-independent sequestration ratio. There were differences in the level of expression and regional distribution of the five receptors: ICAM-1 was the most widely expressed receptor, followed by CD36, VCAM-1, E-selectin, and thrombospondin. Receptor-expressing microvessels were most numerous in the frontal lobe and least numerous in the brainstem and cerebellum. Colocalization of receptor-expressing endothelial cells with iRBC was present in all brain regions; it was highest for ICAM-1 and CD36 and greatest in the frontal lobe. The sequestration ratios were close to 100% for all receptors across all brain regions and were similar in cerebral and extracerebral microvessels. Receptor expression and colocalization ratios were greater in the brain than in the lung, heart, liver, spleen, and subcutaneous tissue. These differences in cerebral endothelial expression of cytoadhesion receptors and their preferential regional distribution may underpin differences in iRBC sequestration and lesion development in CM. Moreover, greater expression of these receptors in the brain vs peripheral organs may explain a comparatively greater degree of iRBC sequestration in the brain.

This review examines the cholinergic (Ch) basal forebrain and its role in neurodegeneration. Terminology used to describe Ch cells and the complex region of the basal forebrain are reviewed. Practical autopsy sampling and labeling strategies for Ch cells are discussed and illustrated with the goal of facilitating diagnostic work and autopsy-based studies of this region. The anatomic connectivity of the system is reviewed with an emphasis placed on the dense cholinergic input to the amygdala, the major target of the Ch basal forebrain, as well as the hippocampus. Ch and basal forebrain neuropathology in various neurodegenerative diseases is then briefly discussed, including more recent studies of TDP-43 proteinopathies. Finally, areas for further study that might further the understanding of the Ch system in neurodegeneration are emphasized.

Myxoid glioneuronal tumor (MGNT) is a recently recognized rare neural tumor in the 2021 WHO Classification of CNS Tumors. Myxoid glioneuronal tumor has low-grade histology and a generally good overall survival rate. However, some tumors exhibit leptomeningeal or intraventricular dissemination at presentation or during disease progression and the underlying biology is unknown. Finding activated signaling pathways and metabolic processes in disseminating MGNTs may reveal potential therapy targets for disseminated tumors. We compared the DNA methylome and transcriptome of disseminating (n = 4) and non-disseminating (n = 7) MGNTs to identify differentially methylated regions and differentially expressed genes. Gene set enrichment analysis (GSEA) was used to identify associated specific signaling and metabolic pathway activation. Myxoid glioneuronal tumors showed similar DNA methylome profiles regardless of dissemination status. Transcription factor MSX1 activation was found in disseminating MGNTs at the transcriptome level. Gene set enrichment analysis revealed the activation of the MAPK, PI3K/AKT/mTOR, MYC, and RAS pathways, as well as multiple metabolic pathways, including OXPHOS, translation, and cell cycle pathways, in disseminating MGNTs. In summary, disseminating MGNT shows simultaneous activation of multiple signaling and metabolic pathways, which may serve as potential therapeutic targets for disseminated disease.