Journal of Neuropathology and Experimental Neurology最新文献

White matter (WM) disruption and atrophy is a consequence of traumatic brain injury (TBI) and contributes to persisting cognitive impairment. An increased expression of the myelin-associated axonal outgrowth inhibitor Nogo-A and oligodendrocyte pathology might be negatively associated with postinjury WM changes. Here, we analyzed brain tissue from severe TBI patients, obtained by surgical decompression in the early postinjury phase and postmortem brain tissue of long-term TBI survivors and observed an increased number of Nogo-A+ cells in WM tracts such as the corpus callosum (CC). Likewise, the number of Nogo-A+ cells in the CC was increased from day 7 postinjury to 6 months postinjury (mpi) following central fluid percussion injury (cFPI) in mice. In addition, the number of Olig2+ cells in the CC and capsula externa remained constant, while the numbers of Olig2+/CC1+ and GST-π+ mature oligodendrocytes declined throughout the observation time of 18 months. A significantly lower number of Olig2+/CC1+ cells was found in cFPI mice compared to controls at 18 mpi. Persistent vulnerability of oligodendrocytes in combination with dynamic alterations of Nogo-A expression may have implications for the WM atrophy and insufficient recovery observed after TBI.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of liver failure. Previous studies described astroglia alterations in HE, but regional changes have not been well investigated. This study addresses regional astroglial response by exploring glial fibrillary acidic protein (GFAP) immunoreactivity in cortical structures including somatosensory (S1Tr and S1BF), piriform (Pir), and perirhinal (PRh) cortices, and subcortical regions including corpus callosum (CC), ventromedial thalamus (VMT), mammillothalamic tract (MTT), and dorsomedial hypothalamic nucleus (DHN) in rats with acute liver failure (ALF) sacrificed at coma stage. Our data showed decreased numbers of astrocytes in S1Tr, Pir, and CC in ALF rats. GFAP-immunoreactive cells were increased within other regions including PRh, VMT, MTT, and DHN. Cell morphometric analysis showed significant increase in GFAP-immunoreactive astrocyte processes and cell bodies in cortical and subcortical regions but not in CC and DHN. However, astrocyte perimeters were increased, particularly in S1Tr and VMT. Our study demonstrates regional specificity including (1) regions with astrocyte activation associated with an increase of GFAP-immunostaining and astrocyte cell counts, together with (2) unaltered GFAP components, and (3) regions characterized by presumably inactive astrocyte with a reduced GFAP-immunostaining. These findings may reflect either different regional alterations in HE, or stages of an alteration progressing differently in different regions.

Presenilin 1 (PSEN1) mutations are the leading cause of early-onset Alzheimer disease (EOAD). A recent study found that the PSEN1 M139I mutation is associated with EOAD. In this study, we examined the impact of the PSEN1 M139I mutation in an EOAD in vitro model. Our findings reveal that the PSEN1 M139I mutation leads to increased levels of Aβ42/40, Hairy and Enhancer of Split-1 (Hes1), neurogenic locus notch homolog intracellular domain, and microRNA-34a, accompanied by a decrease in the level of neurogenic locus notch homolog protein 1 (NOTCH-1). Computational predictions indicate that NOTCH-1 is a direct target of microRNA-34a. Transfection of microRNA-34a mimics into PSEN1 M139I mutant SH-SY5Y cells increased the ratio of Aβ42/40 and induced Hes1, cysteine-aspartic acid protease 3 (Caspase-3), and apoptosis while reducing the NOTCH-1 expression and inhibiting cell proliferation. Conversely, downregulating microRNA-34a expression by transfecting microRNA-34a inhibitors mitigated these effects, thereby restoring NOTCH-1 production and cell proliferation and reversing the increases in Aβ42/40 ratio, Hes1, Caspase-3, and apoptosis induced by the PSEN1 M139I mutation. In summary, the PSEN1 M139I mutation identified in EOAD may influence amyloid-β (Aβ) production and apoptosis by regulating the microRNA-34a-mediated NOTCH-1 signaling pathway.

Chitinase 3-like protein 1 (CHI3L1) is emerging as a promising biomarker for assessing intracranial lesion burden and predicting prognosis in traumatic brain injury (TBI) patients. Following experimental TBI, Chi3l1 transcripts were detected in reactive astrocytes located within the pericontusional cortex. However, the cellular sources of CHI3L1 in response to hemorrhagic contusions in human brain remain unidentified. Hence, we examined a comprehensive collection of histologically defined acute and subacute human cerebral contusions with various surgical intervals using immunohistochemistry, validated through double immunofluorescence for markers such as GFAP, NeuN, MBP, and Iba-1, along with Fluoro-Jade C histofluorescence staining. CHI3L1 was found at meningeal interfaces, showing significant thickening of subpial glial plate. Paradoxically, CHI3L1-positive astrocytes were identified in neuroanatomical locations distant from hemorrhagic foci, where numerous eosinophilic ischemic neurons also exhibited CHI3L1 immunoreactivity. CHI3L1 immunostaining extended into white matter tracts and highlighted various phagocytic or activated microglia forms after delayed surgical decompressions. Given these findings, we advise against using CHI3L1 as a reactive astrogliosis marker due to its expression in multiple cell types, including astrocytes, neurons, oligodendrocytes, ependymocytes, leptomeningeal cells, microglia, and blood vessels. This non-selective response underscores the potential for CHI3L1 elevation patterns in biofluids to reflect the overall lesion burden extent.

In modern war theaters, exposures to blast overpressures are one of the most common causes of brain injury. These pervasive events result in acute and chronic cerebrovascular degenerative processes. Using a rat model of blast-induced mild traumatic brain injury, we identified intramural periarterial hematomas as early primary acute lesions induced by blast exposures. These lesions resulted in intravascular cell death, cell layer reorganization, and plasma leakage into the intraperiarterial basal membranes that constitute the intraperiarterial drainage system (IPAD). Plasma metalloproteases, including MMP-9, in the IPAD basal membranes may degrade extracellular matrix components compromising normal cerebral interstitial fluid drainage, arterial structure and function leading to chronic vascular degenerative processes. Related subacute effects of blast exposure included increased MMP-9 expression in perivascular reactive astrocytes and the extension of astrocytic processes through the layers of affected vessels. These results, in combination with normal levels of proinflammatory cytokines and the absence of proinflammatory MHC II-expressing microglia, suggest an astrocytic role in the clearing of intravascular hematomas and provide further mechanistic evidence that blast-induced vascular degenerative processes may precede the onset of neurovascular inflammation.

Rubinstein-Taybi syndrome (RTS) is a congenital disorder with characteristic clinical manifestations. In the vast majority of cases, it is caused by mutations of the gene encoding the transcriptional co-activator cAMP-response element binding protein (CBP)-binding protein (CREBBP). It has been thought to be a tumor predisposition syndrome as RTS patients have an increased risk of developing tumors including meningiomas. However, RTS-associated meningiomas are rarely reported. We report a unique RTS-associated meningioma in which an oncogenic CREBBP mutation is identified. We also comprehensively review the reported RTS-associated meningiomas, from epidemiology and pathogenesis to clinicopathological characteristics and treatment. All RTS patients with meningiomas are female and have the exclusive mutations of CREBBP. In population-based studies RTS-associated meningiomas seem to develop at younger ages. Their pathogenesis may be driven by the CREBBP/CBP alterations resulting in aberrant signal transduction in the CBP-mediated signaling pathways. Meningiomas in RTS patients have common clinicopathological characteristics including comorbidity with other tumors, radiologically intra-osseous growth, and uncommon histopathology such as ossifying and secretory features. Given the genetic nature and rarity of RTS-associated meningiomas, further investigation of their characteristics may define molecular targets for improved therapeutic options for RTS patients.

The EIF4G1 gene has been considered an autosomal dominant cause of Parkinson disease (PD), even if its role is still debated. The objective of this study was to describe the phenotype and α-synuclein distribution in peripheral tissues in 2 related PD patients (mother and daughter), who are carriers of the same variant in exon 10 of EIF4G1 (c.1216G>A, p.Gly406Arg). We used the Burghart Sniffin Sticks test for olfactory function. α-Synuclein distribution in the olfactory mucosa and skin samples was analyzed using RT-QuIC, double immunofluorescence, and immunohistochemical staining. Both patients presented with a mild motor syndrome associated with hyposmia as prominent traits; pathological α-synuclein deposits were found in the olfactory mucosa but not in the skin. The phenotype and the findings in peripheral tissues suggest that PARK18 could manifest as a "benign" form of PD associated with hyposmia, with a slow progression and sparse α-synuclein accumulation in the peripheral nervous system.

Trans-active response DNA-binding protein-43 (TDP-43) is the major pathological protein in motor neuron disease and TDP-43 pathology has been described in the brains of up to 50% of patients with Alzheimer disease (AD). Hippocampal sclerosis of aging (HS-A), an age-related neuropathology characterized by severe neuronal loss and gliosis in CA1 and/or subiculum, is found in ∼80% of cases that are positive for phosphorylated TDP-43. HS-A is seen as a co-pathology in cases with AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), and frontotemporal degeneration. To understand the pathogenetic relationships between HS-A and LATE-NC, mice that selectively express human TDP-43 and TDP-43 with a defective nuclear localization signal (ΔNLS) in the hippocampus, alone or in an APP/PSEN1 background, were evaluated using histology, HALO software's object recognition algorithms, and protein expression assays. Twenty-four-month-old mice expressing cytosolic TDP-43 displayed marked neuronal loss and atrophy in the hippocampus, decreased β-amyloid plaque deposition and modulation of microglia and intermediate filament activation. TDP-43ΔNLS-expressing mice survived to only ∼24 months of age whether or not they had an APP/PSEN1 background. This HS-A-like model may provide insights into the pathogenesis of neurodegeneration seen in HS-A and in other TDP-43 proteinopathies.