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Synaptic Dysfunction (synaptic + dysfunction)
Selected AbstractsProteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque depositionPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2007Frank Gillardon Dr. Abstract Synaptic dysfunction is an early event in Alzheimer's disease patients and has also been detected in transgenic mouse models. In the present study, we analyzed proteomic changes in synaptosomal fractions from Tg2576 mice that overexpress mutant human amyloid precursor protein (K670N, M671L) and from their nontransgenic littermates. Cortical and hippocampal tissue was microdissected at the onset of cognitive impairment, but before deposition of amyloid plaques. Crude synaptosomal fractions were prepared by differential centrifugation, proteins were separated by 2-D DIGE and identified by MS/MS. Significant alterations were detected in mitochondrial heat shock protein 70 pointing to a mitochondrial stress response. Subsequently, synaptosomal versus nonsynaptic mitochondria were purified from Tg2576 mice brains by density gradient centrifugation. Mitochondrial proteins were separated by IEF or Blue-native gel electrophoresis in the first dimension and SDS-PAGE in the second dimension. Numerous changes in the protein subunit composition of the respiratory chain complexes I and III were identified. Levels of corresponding mRNAs remain unchanged as shown by Affymetrix oligonucleotide array analysis. Functional examination revealed impaired state 3 respiration and uncoupled respiration in brain mitochondria from young Tg2576 mice. By immunoblotting, amyloid-beta oligomers were detected in synaptosomal fractions from Tg2576 mice and reduced glucose metabolism was observed in Tg2576 mice brains by [14C]-2-deoxyglucose infusion. Taken together, we demonstrate alterations in the mitochondrial proteome and function that occur in Tg2576 mice brains before amyloid plaque deposition suggesting that mitochondria are early targets of amyloid-beta aggregates. [source] Oxidative stress activates a positive feedback between the ,- and ,-secretase cleavages of the ,-amyloid precursor proteinJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Elena Tamagno Abstract Sequential cleavages of the ,-amyloid precursor protein cleaving enzyme 1 (BACE1) by ,-secretase and ,-secretase generate the amyloid ,-peptides, believed to be responsible of synaptic dysfunction and neuronal cell death in Alzheimer's disease (AD). Levels of BACE1 are increased in vulnerable regions of the AD brain, but the underlying mechanism is unknown. Here we show that oxidative stress (OS) stimulates BACE1 expression by a mechanism requiring ,-secretase activity involving the c- jun N-terminal kinase (JNK)/c- jun pathway. BACE1 levels are increased in response to OS in normal cells, but not in cells lacking presenilins or amyloid precursor protein. Moreover, BACE1 is induced in association with OS in the brains of mice subjected to cerebral ischaemia/reperfusion. The OS-induced BACE1 expression correlates with an activation of JNK and c- jun, but is absent in cultured cells or mice lacking JNK. Our findings suggest a mechanism by which OS induces BACE1 transcription, thereby promoting production of pathological levels of amyloid , in AD. [source] Alpha-synuclein overexpression in mice alters synaptic communication in the corticostriatal pathwayJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2010Nanping Wu Abstract ,-Synuclein (,-Syn) is a presynaptic protein implicated in Parkinson's disease (PD). Mice overexpressing human wildtype (WT) ,-Syn under the Thy1 promoter show high levels of ,-Syn in cortical and subcortical regions, exhibit progressive sensorimotor anomalies, as well as non-motor abnormalities and are considered models of pre-manifest PD as there is little evidence of early loss of dopaminergic (DA) neurons. We used whole-cell patch clamp recordings from visually identified striatal medium-sized spiny neurons (MSSNs) in slices from ,-Syn and WT littermate control mice at 35, 90 and 300 days of age to examine corticostriatal synaptic function. MSSNs displayed significant decreases in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in ,-Syn mice at all ages. This difference persisted in the presence of tetrodotoxin, indicating it was independent of action potentials. Stimulation thresholds for evoking EPSCs were significantly higher and responses were smaller in ,-Syn mice. These data suggest a decrease in neurotransmitter release at the corticostriatal synapse. At 90 days the frequency of spontaneous GABAA receptor-mediated synaptic currents was decreased in MSSNs but increased in cortical pyramidal neurons. These observations indicate that high levels of expression of ,-Syn alter corticostriatal synaptic function early and they provide evidence for early synaptic dysfunction in a pre-manifest model of PD. Of importance, these changes are opposite to those found in DA-depletion models, suggesting that before degeneration of DA neurons in the substantia nigra synaptic adaptations occur at the corticostriatal synapse that may initiate subtle preclinical manifestations. © 2009 Wiley-Liss, Inc. [source] Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivoJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2006Rime Madani Abstract Accumulation of the ,-amyloid peptide (A,) in the brain is a major pathological hallmark of Alzheimer's disease (AD), leading to synaptic dysfunction, neuronal death, and memory impairment. The levels of neprilysin, a major A,-degrading enzyme, are decreased in AD brains and during aging. Because neprilysin cleaves A, in vivo, its down-regulation may contribute to the pathophysiology of AD. The aim of this study was to assess the consequences of neprilysin deficiency on accumulation of murine A, in brains and associated pathologies in vivo by investigating neprilysin-deficient mice on biochemical, morphological, and behavioral levels. Aged neprilysin-deficient mice expressed physiological amyloid precursor protein (APP) levels and exhibited elevated brain A, concentrations and amyloid-like deposits in addition to signs of neuronal degeneration in their brains. Behaviorally, neprilysin-deficient mice acquired a significantly weaker conditioned taste aversion that extinguished faster than the aversion of age-matched controls. Our data establish that, under physiological APP expression levels, neprilysin deficiency is associated with increased A, accumulation in the brain and leads to deposition of amyloid-like structures in vivo as well as with signs of AD-like pathology and with behavioral deficits. © 2006 Wiley-Liss, Inc. [source] MicroRNA and proteome expression profiling in early-symptomatic ,-synuclein(A30P)-transgenic micePROTEOMICS - CLINICAL APPLICATIONS, Issue 5 2008Frank Gillardon Dr. Abstract The ,-synuclein has been implicated in the pathophysiology of Parkinson's disease (PD), because mutations in the alpha-synuclein gene cause autosomal-dominant hereditary PD and fibrillary aggregates of alpha-synuclein are the major component of Lewy bodies. Since presynaptic accumulation of ,-synuclein aggregates may trigger synaptic dysfunction and degeneration, we have analyzed alterations in synaptosomal proteins in early symptomatic ,-synuclein(A30P)-transgenic mice by two-dimensional differential gel electrophoresis. Moreover, we carried out microRNA expression profiling using microfluidic chips, as microRNA have recently been shown to regulate synaptic plasticity in rodents and to modulate polyglutamine-induced protein aggregation and neurodegeneration in flies. Differentially expressed proteins in ,-synuclein(A30P)-transgenic mice point to alterations in mitochondrial function, actin dynamics, iron transport, and vesicle exocytosis, thus partially resembling findings in PD patients. Oxygen consumption of isolated brain mitochondria, however, was not reduced in mutant mice. Levels of several microRNA (miR-10a, -10b, -212, -132, -495) were significantly altered. One of them (miR-132) has been reported to be highly inducible by growth factors and to be a key regulator of neurite outgrowth. Moreover, miR-132-recognition sequences were detected in the mRNA transcripts of two differentially expressed proteins. MicroRNA may thus represent novel biomarkers for neuronal malfunction and potential therapeutic targets for human neurodegenerative diseases. [source] Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-, oligomersANNALS OF NEUROLOGY, Issue 6 2006Matthew Townsend PhD Objective Despite progress in defining a pathogenic role for amyloid , protein (A,) in Alzheimer's disease, orally bioavailable compounds that prevent its effects on hippocampal synaptic plasticity and cognitive function have not yet emerged. A particularly attractive therapeutic strategy is to selectively neutralize small, soluble A, oligomers that have recently been shown to mediate synaptic dysfunction. Methods Using electrophysiological, biochemical, and behavioral assays, we studied how scyllo -inositol (AZD-103; molecular weight, 180) neutralizes the acutely toxic effects of A, on synaptic function and memory recall. Results Scyllo -inositol, but not its stereoisomer, chiro -inositol, dose-dependently rescued long-term potentiation in mouse hippocampus from the inhibitory effects of soluble oligomers of cell-derived human A,. Cerebroventricular injection into rats of the soluble A, oligomers interfered with learned performance on a complex lever-pressing task, but administration of scyllo -inositol via the drinking water fully prevented oligomer-induced errors. Interpretation A small, orally available natural product penetrates into the brain in vivo to rescue the memory impairment produced by soluble A, oligomers through a mechanism that restores hippocampal synaptic plasticity. Ann Neurol 2006;60:668,676 [source] | ||||||||||