809 research outputs found

    Identification of a novel mutation in MEF2C gene in an atypical patient with frontotemporal lobar degeneration

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    The MEF2C gene encodes a transcription factor known to play a crucial role in molecular pathways affecting neuronal development. MEF2C mutations were described as a genetic cause of developmental disease (MRD20), and several reports sustain its involvement in dementia-related conditions, such as Alzheimer's disease and amyotrophic lateral sclerosis. These pathologies and frontotemporal degeneration (FTLD) are thought to share common physiopathological pathways. In this exploratory study, we searched for alterations in the DNA sequence of exons and boundaries, including 5 '- and 3 '-untranslated regions (5 ' UTR, 3 ' UTR), of MEF2C gene in 11 patients with clinical phenotypes related with MRD20 or FTLD. We identified a heterozygous deletion of 13 nucleotides in the 5 ' UTR region of a 69 years old FTLD patient. This alteration was absent in 200 healthy controls, suggesting a contribution to this patient's disease phenotype. In silico analysis of the mutated sequence indicated changes in mRNA secondary structure and stability, thus potentially affecting MEF2C protein levels. Furthermore, in vitro functional analysis of this mutation revealed that the presence of this deletion abolished the transcriptional activity of the gene in human embryonic cells and rat brain neurons, probably by modifying MEF2C expression. Altogether, our results provide evidence for the involvement of MEF2C in FTLD manifesting with seizures.European Regional Development Fund (ERDF) through the COMPETE - Operational Competitiveness Program; FCT Foundation for Science and TechnologyPortuguese Foundation for Science and Technology [PEst-C/SAU/LA0001/2013-2014

    Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aő≤ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice

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    Vascular dysregulation and cholinergic basal forebrain degeneration are both early pathological events in the development of Alzheimer‚Äôs disease (AD). Acetylcholine contributes to localised arterial dilatation and increased cerebral blood flow (CBF) during neurovascular coupling via activation of endothelial nitric oxide synthase (eNOS). Decreased vascular reactivity is suggested to contribute to impaired clearance of ő≤-amyloid (Aő≤) along intramural periarterial drainage (IPAD) pathways of the brain, leading to the development of cerebral amyloid angiopathy (CAA). However, the possible relationship between loss of cholinergic innervation, impaired vasoreactivity and reduced clearance of Aő≤ from the brain has not been previously investigated. In the present study, intracerebroventricular administration of mu-saporin resulted in significant death of cholinergic neurons and fibres in the medial septum, cortex and hippocampus of C57BL/6 mice. Arterial spin labelling MRI revealed a loss of CBF response to stimulation of eNOS by the Rho-kinase inhibitor fasudil hydrochloride in the cortex of denervated mice. By contrast, the hippocampus remained responsive to drug treatment, in association with altered eNOS expression. Fasudil hydrochloride significantly increased IPAD in the hippocampus of both control and saporin-treated mice, while increased clearance from the cortex was only observed in control animals. Administration of mu-saporin in the TetOAPPSweInd mouse model of AD was associated with a significant and selective increase in Aő≤40-positive CAA. These findings support the importance of the interrelationship between cholinergic innervation and vascular function in the aetiology and/or progression of CAA and suggest that combined eNOS/cholinergic therapies may improve the efficiency of Aő≤ removal from the brain and reduce its deposition as CAA

    Molecular abnormalities in autopsied brain tissue from the inferior horn of the lateral ventricles of nonagenarians and Alzheimer disease patients

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    Background The ventricular system plays a vital role in blood-cerebrospinal fluid (CSF) exchange and interstitial fluid-CSF drainage pathways. CSF is formed in the specialized secretory tissue called the choroid plexus, which consists of epithelial cells, fenestrated capillaries and the highly vascularized stroma. Very little is currently known about the role played by the ventricles and the choroid plexus tissue in aging and Alzheimer's disease (AD). MethodsIn this study, we used our state-of-the-art proteomic platform, a liquid chromatography/mass spectrometry (LC-MS/MS) approach coupled with Tandem Mass Tag isobaric labeling to conduct a detailed unbiased proteomic analyses of autopsied tissue isolated from the walls of the inferior horn of the lateral ventricles in AD (77.2 ¬Ī 0.6‚ÄČyrs), age-matched controls (77.0 ¬Ī 0.5‚ÄČyrs), and nonagenarian cases (93.2 ¬Ī 1.1‚ÄČyrs). ResultsIngenuity pathway analyses identified phagosome maturation, impaired tight-junction signaling, and glucose/mannose metabolism as top significantly regulated pathways in controls vs nonagenarians. In matched-control vs AD cases we identified alterations in mitochondrial bioenergetics, oxidative stress, remodeling of epithelia adherens junction, macrophage recruitment and phagocytosis, and cytoskeletal dynamics. Nonagenarian vs AD cases demonstrated augmentation of oxidative stress, changes in gluconeogenesis-glycolysis pathways, and cellular effects of choroidal smooth muscle cell vasodilation. Amyloid plaque score uniquely correlated with remodeling of epithelial adherens junctions, Fc ő≥-receptor mediated phagocytosis, and alterations in RhoA signaling. Braak staging was uniquely correlated with altered iron homeostasis, superoxide radical degradation and phagosome maturation. Conclusions These changes provide novel insights to explain the compromise to the physiological properties and function of the ventricles/choroid plexus system in nonagenarian aging and AD pathogenesis. The pathways identified could provide new targets for therapeutic strategies to mitigate the divergent path towards AD

    Metabolic Syndrome and Cardiovascular Disease Impacts on the Pathophysiology and Phenotype of HIV-Associated Neurocognitive Disorders

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    International audienceAbstract Evidence from epidemiological studies on the general population suggests that midlife cardiovascular disease (CVD) and/or metabolic syndrome (MetS) are associated with an increased risk of cognitive impairment and dementia later in life. In the modern combined antiretroviral therapy (cART) era, as in the general population, CVD and MetS were strongly and independently associated with poorer cognitive performances of sustained immunovirologically controlled persons living with human immunodeficiency viruses (PLHIVs). Those findings suggest that CV/metabolic comorbidities could be implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND) and might be more important than factors related to HIV infection or its treatment, markers of immunocompetence, or virus replication. The association between CVD/MetS and cognition decline is driven by still not well-understood mechanisms, but risk might well be the consequence of increased brain inflammation and vascular changes, notably cerebral small-vessel disease. In this review, we highlight the correspondences observed between the findings concerning CVD and MetS in the general population and virus-suppressed cART-treated PLHIVs to evaluate the real brain-aging processes. Indeed, incomplete HIV control mainly reflects HIV-induced brain damage described during the first decades of the pandemic. Given the growing support that CVD and MetS are associated with HAND, it is crucial to improve early detection and assure appropriate management of these conditions

    The reticular formation and the neuromodulatory systems

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    Almost a century ago, Constantin von Economo observed that in patients with encephalitis lethargica lesions in the upper brain stem and posterior hypothalamus impaired consciousness. From lesion studies in cats and anatomical data, the idea arose that the brain stem reticular formation is the origin of the ascending reticular activating system (ARAS) that would operate through the intralaminar nuclei and activate widespread regions of the cerebral cortex. This view of the reticular formation has been extensively modified, and nowadays the reticular formation is viewed as a series of highly specific cell groups, which closely surround the individual motor and sensory nuclei of the brain stem (Sects. 5.2 and 5.4). The diffuse system, driving arousal and consciousness, is now attributed to the neuromodulatory system, including the serotonergic raphe nuclei, the locus coeruleus and other noradrenergic or adrenergic cell groups and cholinergic cell groups, all close to the reticular formation (Sects. 5.3 and 5.5). The English terms of the Terminologia Neuroanatomica are used throughout. Although the basic notion of the ARAS concept that structures in the brain stem regulate states of consciousness still holds true, a much more complex picture has emerged. Experimental work in laboratory animals suggests that the following structures play key roles in the maintenance and modulation of wakefulness: cholinergic nuclei in the upper brain stem and basal forebrain; noradrenergic nuclei, in particular the locus coeruleus; a histaminergic projection from the tuberomamillary nucleus in the posterior hypothalamus; and dopaminergic and serotonergic pathways from the ventral tegmental area and raphe nuclei, respectively. These nuclei all participate in an ascending activating system to the cerebral cortex (Sect. 5.5). The hypothalamus also contains orexinergic neurons that are crucial for maintaining normal wakefulness and a sleep-promoting region in the ventrolateral preoptic area. These groups have mutually inhibiting connections, known as the sleep switch (Sect. 5.6). Some sleep disorders in which these structures are involved are discussed in Clinical Cases (Sect. 5.7). Damage to the upper brain stem reticular formation is known to cause the most radical disturbance of consciousness, i.e. coma, as illustrated in several Clinical Cases (Sect. 5.8)

    Evidence for a Dynorphin-mediated Inner Ear Immune/Inflammatory Response and Glutamate-induced Neural Excitotoxicity: An Updated Analysis

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    Acoustic overstimulation (AOS) is defined as the stressful overexposure to high-intensity sounds. AOS is a precipitating factor that leads to a glutamate (GLU)-induced Type I auditory neural excitotoxicity and an activation of an immune/inflammatory/oxidative stress response within the inner ear, often resulting in cochlear hearing loss. The dendrites of the Type I auditory neural neurons that innervate the inner hair cells (IHCs), and respond to the IHC release of the excitatory neurotransmitter GLU, are themselves directly innervated by the dynorphin (DYN)-bearing axon terminals of the descending brain stem lateral olivocochlear (LOC) system. DYNs are known to increase GLU availability, potentiate GLU excitotoxicity, and induce superoxide production. DYNs also increase the production of proinflammatory cytokines by modulating immune/inflammatory signal transduction pathways. Evidence is provided supporting the possibility that the GLU-mediated Type I auditory neural dendritic swelling, inflammation, excitotoxicity, and cochlear hearing loss that follow AOS may be part of a brain stem-activated, DYN-mediated cascade of inflammatory events subsequent to a LOC release of DYNs into the cochlea. In support of a DYN-mediated cascade of events are established investigations linking DYNs to the immune/inflammatory/excitotoxic response in other neural systems

    Molecular Chaperones and Protein Quality Control System in the Canine Model of Brain Aging and Neurodegenerative Diseases

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    Aged dogs naturally develop cognitive dysfunction and represent a valuable spontaneous animal model for studying normal aging and neurodegeneration. Elderly canines also share neuropathological hallmarks similar to those observed in humans, especially Alzheimer’s disease-like pathology or amyotrophic lateral sclerosis. In addition, pet dogs share similar living conditions and diets to humans. Increasing oxidative damage, as well as alterations of the intracellular protein quality control system, including ubiquitin-proteasome system (UPS) and Heat shock proteins (Hsp), have been observed in the brain of aged dogs. Thus, future researches carried out on the canine spontaneous model may be useful to define the involvement of age-related alterations in Hsp expression and UPS activity in the pathogenesis of neurodegenerative diseases, as well as to perform translational antioxidant treatment/prevention studies. The possibility to design novel therapeutic approaches, including Hspbased therapies, may help to increase chaperone protection against proteotoxic stress occurring in human and canine brain during aging

    Neurodegenerative Diseases and Ageing

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