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Oral submucous fibrosis (OSF) is a chronic insidious disease which predisposes to oral cancer. Understanding the molecular markers for OSF is critical for diagnosis and treatment of oral cancer. In this study, the proteins expression profile of OSF tissues was compared to normal mucous tissues by 2 dimensional electrophoresis (2-DE). The 2-DE images were analyzed through cut, spot detection and match analysis using mass spectrometry (MS). Differentially expressed genes were identified as candidates. RT-PCR, Western Blot and immunohistochemistry were performed to validate the difference in expression of the candidates between OSF and normal mucous tissues. The shRNA targeted to the candidates were then transfected by Lipofectamine2000 to the 3T3 cells to study gene function. Cell proliferation and apoptosis were measured by MTT, clonogenic formation, PI and TUNEL staining. From the proteomic analysis, 94 of the 182 selected spots with differential expression were identified by MS analysis and Cyclophilin A (CYPA) was determined to be the OSF-associated protein candidate. The significant differences in expression between OSF and normal tissues were verified and confirmed by RT-PCR, Western blot and Immunohistochemical analysis. Inhibition of CYPA expression by RNA interference suggested its potential activities involved in cell proliferation and apoptosis process. In conclusion, these results indicated a novel molecular mechanism of OSF pathogenesis and demonstrated CYPA as a potential biomarker and gene intervention targets of OSF. These data may help the development for therapeutics of oral cancer.

Concepts: DNA, Protein, Gene, Gene expression, Bacteria, Molecular biology, RNA, Laboratory techniques

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This study aims to discuss clinical characteristics, image manifestation and treatment methods of temporal bone lesions with facial paralysis as the main manifestation for deepening the understanding of such type of lesions and reducing erroneous and missed diagnosis.

Concepts: Skull, Logic

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Patients with Alzheimer’s disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown.

Concepts: Alzheimer's disease, Epidemiology, Neurology, Parkinson's disease, Dementia, Lewy body, Dementia with Lewy bodies, Frontotemporal lobar degeneration

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Increasing evidence suggests that neuroinflammation comprises a major characteristic of Alzheimer’s disease (AD). Tumor necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine implicated in neurodegenerative diseases including AD, and has been proposed as a potent therapeutic target for AD. Although a number of studies focusing on pharmacological or genetic manipulation of TNF-α and its receptors in AD mice have provided significant knowledge regarding the role of TNF-α signaling pathway in the pathogenesis of AD, the consequences of TNF-α genetic deletion have not been thoroughly examined. Here, we focused on the effect of TNF-α deficiency on the amyloid phenotype of 5XFAD mice. Our analysis revealed that amyloid deposition, amyloid-β (Aβ) levels, and AβPP-carboxyterminal fragments are significantly reduced in the brains of 5XFAD/TNF-α-/- mice compared to the 5XFAD/TNF-α+/+. We found decreased protein levels of β- and α-secretases in the 5XFAD/TNF-α-/- brains, suggesting for an effect of TNF-α on AβPP processing and Aβ generation. We also show for the first time that TNF-α affects PS1in vivo, as 5XFAD mice lacking TNF-α expression display reduced PS1-carboxyterminal fragments implying for diminished PS1 activity. Moreover, TNF-α deficiency decreases microglial and astrocytic activation and significantly restricts the phagocytic activity of macrophages against Aβ, supporting for reduced responsiveness of phagocytes toward Aβ. Overall, our results reveal that TNF-α genetic deletion in 5XFAD mice attenuates amyloid plaque formation by lowering Aβ generation through the reduction of functionally active PS1 and β-secretase rather than promoting Aβ clearance by phagocytic cells. Our data further suggest TNF-α inhibition as a therapeutic approach for AD.

Concepts: Immune system, DNA, Gene, Genetics, Phagocytosis, Amyloid, Beta amyloid, Phagocyte

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The clinical and structural trajectories of suspected non-Alzheimer' pathology (SNAP) remain elusive due to its heterogeneous etiology. Baseline and longitudinal clinical (global cognition, daily functioning, symptoms of dementia, and learning memory) and hippocampal volume trajectories over two years were compared between patients with amnestic mild cognitive impairment (aMCI) with SNAP with reduced hippocampal volumes (SNAP+HIPPO) and aMCI patients with SNAP without reduced hippocampal volumes. SNAP+HIPPO showed overall worse baseline cognitive functions. Longitudinally, SNAP+HIPPO showed faster deterioration of clinical symptoms of dementia. Having both hippocampal atrophy and cortical hypometabolism without amyloid pathology may exacerbate symptoms of dementia in aMCI.

Concepts: Alzheimer's disease, Psychology, Brain, Cognition, Memory, Hippocampus, Psychiatry, Amnesia

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Impaired cardiac function has been related to accelerated cognitive decline in late-life.

Concepts: Cognition, Educational psychology, Troponin, Troponin T

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Co-existence of Alzheimer’s disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

Concepts: Alzheimer's disease, Neurocognitive, Neurology, Dementia, Cerebrospinal fluid, Beta amyloid, Hydrocephalus, Normal pressure hydrocephalus

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While APOEɛ4 is the major genetic risk factor for Alzheimer’s disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aβ42 (pAβ) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics' referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAβ and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAβ compared to NC, and cases recruited from memory clinics had higher fractions of pAβ and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAβ enriched, whereas self-referred and NCFD cases more frequently are pAβ negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Concepts: Alzheimer's disease, Cognition, Memory, Apolipoprotein E, Dementia, Semantic memory, Caregiving and dementia, Mild cognitive impairment

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Weight loss is frequently observed in patients with Alzheimer’s disease (AD); however, the underlying mechanisms are not well understood.

Concepts: Alzheimer's disease, Protein, Medicine, Nutrition, Mitochondrion, Fat, Glycogen, Carbohydrate

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Extracellular vesicles (EVs), including exosomes and larger microvesicles, have been implicated to play a role in several conditions, including Alzheimer’s disease (AD). Since the EV content mirrors the intracellular environment, it could contribute with important information about ongoing pathological processes and may be a useful source for biomarkers, reflecting the disease progression. The aim of the present study was to analyze the protein content of EVs specifically released from a mixed co-culture of primary astrocytes, neurons, and oligodendrocytes treated with synthetic amyloid-β (Aβ42) protofibrils. The EV isolation was performed by ultracentrifugation and validated by transmission electron microscopy. Mass spectrometry analysis of the EV content revealed a total of 807 unique proteins, of which five displayed altered levels in Aβ42 protofibril exposed cultures. The most prominent protein was apolipoprotein E (apoE), and by western blot analysis we could confirm a threefold increase of apoE in EVs from Aβ42 protofibril exposed cells, compared to unexposed cells. Moreover, immunoprecipitation studies demonstrated that apoE was primarily situated inside the EVs, whereas immunocytochemistry indicated that the EVs most likely derived from the astrocytes and the neurons in the culture. The identified Aβ-induced sorting of apoE into EVs from cultured neuroglial cells suggests a possible role for intercellular transfer of apoE in AD pathology and encourage future studies to fully elucidate the clinical relevance of this event.

Concepts: Alzheimer's disease, Protein, Molecular biology, Mass spectrometry, Cell membrane, Cell biology, Western blot, Apolipoprotein E