Home About us Contact
|
Home About us Contact | ||
|
|
||
Synaptic Loss (synaptic + loss)
Selected AbstractsAlcohol-Induced Neurodegeneration: When, Where and Why?ALCOHOLISM, Issue 2 2004Fulton T. Crews Abstract: This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were (1) Characterization of Synaptic Loss in Cerebella of Mature and Senescent Rats after Lengthy Chronic Ethanol Consumption, (2) Ethanol Withdrawal Both Causes Neurotoxicity and Inhibits Neuronal Recovery Processes in Rat Organotypic Hippocampal Cultures, (3) Binge Drinking-Induced Brain Damage: Genetic and Age Related Effects, (4) Binge Ethanol-Induced Brain Damage: Involvement of Edema, Arachidonic Acid and Tissue Necrosis Factor , (TNF,), and (5) Cyclic AMP Cascade, Stem Cells and Ethanol. Taken together these studies suggest that alcoholic neurodegeneration occurs through multiple mechanisms and in multiple brain regions both during intoxication and withdrawal. [source] Loss of translation elongation factor (eEF1A2) expression in vivo differentiates between Wallerian degeneration and dying-back neuronal pathologyJOURNAL OF ANATOMY, Issue 6 2008Lyndsay M. Murray Abstract Wallerian degeneration and dying-back pathology are two well-known cellular pathways capable of regulating the breakdown and loss of axonal and synaptic compartments of neurons in vivo. However, the underlying mechanisms and molecular triggers of these pathways remain elusive. Here, we show that loss of translation elongation factor eEF1A2 expression in lower motor neurons and skeletal muscle fibres in homozygous Wasted mice triggered a dying-back neuropathy. Synaptic loss at the neuromuscular junction occurred in advance of axonal pathology and by a mechanism morphologically distinct from Wallerian degeneration. Dying-back pathology in Wasted mice was accompanied by reduced expression levels of the zinc finger protein ZPR1, as found in other dying-back neuropathies such as spinal muscular atrophy. Surprisingly, experimental nerve lesion revealed that Wallerian degeneration was significantly delayed in homozygous Wasted mice; morphological assessment revealed that ~80% of neuromuscular junctions in deep lumbrical muscles at 24 h and ~50% at 48 h had retained motor nerve terminals following tibial nerve lesion. This was in contrast to wild-type and heterozygous Wasted mice where < 5% of neuromuscular junctions had retained motor nerve terminals at 24 h post-lesion. These data show that eEF1A2 expression is required to prevent the initiation of dying-back pathology at the neuromuscular junction in vivo. In contrast, loss of eEF1A2 expression significantly inhibited the initiation and progression of Wallerian degeneration in vivo. We conclude that loss of eEF1A2 expression distinguishes mechanisms underlying dying-back pathology from those responsible for Wallerian degeneration in vivo and suggest that eEF1A2 -dependent cascades may provide novel molecular targets to manipulate neurodegenerative pathways in lower motor neurons. [source] Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze trainingEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2003Carmen Sandi Abstract The impact was examined of exposing rats to two life experiences of a very different nature (stress and learning) on synaptic structures in hippocampal area CA3. Rats were subjected to either (i) chronic restraint stress for 21 days, and/or (ii) spatial training in a Morris water maze. At the behavioural level, restraint stress induced an impairment of acquisition of the spatial response. Moreover, restraint stress and water maze training had contrasting impacts on CA3 synaptic morphometry. Chronic stress induced a loss of simple asymmetric synapses [those with an unperforated postsynaptic density (PSD)], whilst water maze learning reversed this effect, promoting a rapid recovery of stress-induced synaptic loss within 2,3 days following stress. In addition, in unstressed animals a correlation was found between learning efficiency and the density of synapses with an unperforated PSD: the better the performance in the water maze, the lower the synaptic density. Water maze training increased the number of perforated synapses (those with a segmented PSD) in CA3, both in stressed and, more notably, in unstressed rats. The distinct effects of stress and learning on CA3 synapses reported here provide a neuroanatomical basis for the reported divergent effects of these experiences on hippocampal synaptic activity, i.e. stress as a suppressor and learning as a promoter of synaptic plasticity. [source] Neurodegeneration in an A,-induced model of Alzheimer's disease: the role of Cdk5AGING CELL, Issue 1 2010Joao P. Lopes Summary Cdk5 dysregulation is a major event in the neurodegenerative process of Alzheimer's disease (AD). In vitro studies using differentiated neurons exposed to A, exhibit Cdk5-mediated tau hyperphosphorylation, cell cycle re-entry and neuronal loss. In this study we aimed to determine the role of Cdk5 in neuronal injury occurring in an AD mouse model obtained through the intracerebroventricular (icv) injection of the A,1,40 synthetic peptide. In mice icv-injected with A,, Cdk5 activator p35 is cleaved by calpains, leading to p25 formation and Cdk5 overactivation. Subsequently, there was an increase in tau hyperphosphorylation, as well as decreased levels of synaptic markers. Cell cycle reactivation and a significant neuronal loss were also observed. These neurotoxic events in A,-injected mice were prevented by blocking calpain activation with MDL28170, which was administered intraperitoneally (ip). As MDL prevents p35 cleavage and subsequent Cdk5 overactivation, it is likely that this kinase is involved in tau hyperphosphorylation, cell cycle re-entry, synaptic loss and neuronal death triggered by A,. Altogether, these data demonstrate that Cdk5 plays a pivotal role in tau phosphorylation, cell cycle induction, synaptotoxicity, and apoptotic death in postmitotic neurons exposed to A, peptides in vivo, acting as a link between diverse neurotoxic pathways of AD. [source] A novel effect of rivastigmine on pre-synaptic proteins and neuronal viability in a neurodegeneration model of fetal rat primary cortical cultures and its implication in Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 4 2010Jason A. Bailey J. Neurochem. (2010) 112, 843,853. Abstract Alzheimer's disease (AD) is characterized by deposition of amyloid-, peptide plaque, disrupted amyloid-,-precursor protein (APP) metabolism, hyperphosphorylation of Tau leading to neurofibrillary tangles and associated neurotoxicity. Moreover, there is synaptic loss in AD, which occurs early and may precede frank amyloidosis. The central cholinergic system is especially vulnerable to the toxic events associated with AD, and reduced acetylcholine levels in specific brain regions is thought to be central to memory deficits in AD. First-generation cholinesterase inhibitors have provided only symptomatic relief to patients with AD by prolonging the action of remaining acetylcholine with little or no change in the course of the disease. Some second-generation cholinesterase inhibitors are multifunctional drugs that may provide more than purely palliative results. To evaluate the effects of the dual acetylcholinesterase and butyrylcholinesterase inhibitor rivastigmine on key aspects of AD, embryonic day 16 rat primary cortical cultures were treated with rivastigmine under media conditions observed to induce time-dependent neurodegeneration. Samples were subjected to western blotting and immunocytochemistry techniques to determine what influence this drug may have on synaptic proteins and neuronal morphology. There was a strong increase in relative cell viability associated with rivastigmine treatment. Significant dose-dependent increases were observed in the levels of synaptic markers synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin, as well as the neuron-specific form of enolase. Together with an observed enhancement of neuronal morphology, our results suggest a rivastigmine-mediated novel neuroprotective and/or neurorestorative effects involving the synapse. Our observations may explain the potential for rivastigmine to alter the course of AD, and warrant further investigations into using butyrylcholinesterase inhibition as a therapeutic strategy for AD, especially with regard to restoration of synaptic function. [source] The neuropathogenic contributions of lysosomal dysfunctionJOURNAL OF NEUROCHEMISTRY, Issue 3 2002Ben A. Bahr Abstract Multiple lines of evidence implicate lysosomes in a variety of pathogenic events that produce neurodegeneration. Genetic mutations that cause specific enzyme deficiencies account for more than 40 lysosomal storage disorders. These mostly pre-adult diseases are associated with abnormal brain development and mental retardation. Such disorders are characterized by intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases including (i) Alzheimer's disease and related tauopathies (ii) Lewy body disorders and synucleinopathies such as Parkinson's disease, and (iii) Huntington's disease and other polyglutamine expansion disorders. Of particular interest for this review is evidence that alterations to the lysosomal system contribute to protein deposits associated with different types of age-related neurodegeneration. Lysosomes are in fact highly susceptible to free radical oxidative stress in the aging brain, leading to the gradual loss of their processing capacity over the lifespan of an individual. Several studies point to this lysosomal disturbance as being involved in amyloidogenic processing, formation of paired helical filaments, and the aggregation of ,-synuclein and mutant huntingtin proteins. Most notably, experimentally induced lysosomal dysfunction, both in vitro and in vivo, recapitulates important pathological features of age-related diseases including the link between protein deposition and synaptic loss. [source] Synapse loss in dementiasJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2010Ryan Clare Abstract Synaptic transmission is essential for nervous system function, and its dysfunction is a known major contributing factor to Alzheimer's-type dementia. Antigen-specific immunochemical methods are able to characterize synapse loss in dementia through the quantification of various synaptic proteins involved in the synaptic cycle. These immunochemical methods applied to the study of Alzheimer's disease (AD) brain specimens have correlated synaptic loss with particularly toxic forms of amyloid-, protein and have also established synapse loss as the best correlate of dementia severity. A significant but comparatively circumscribed amount of literature describes synaptic decline in other forms of dementia. Ischemic vascular dementia (IVD) is quite heterogeneous, and synapse loss in IVD seems to be variable among IVD subtypes, probably reflecting its variable neuropathologic correlates. Loss of synaptic protein has been identified in vascular dementia of the Binswanger type and Spatz-Lindenberg's disease. Here we demonstrate a significant loss of synaptophysin density within the temporal lobe of frontotemporal dementia (FTD) patients. © 2010 Wiley-Liss, Inc. [source] Redox proteomics studies of in vivo amyloid beta-peptide animal models of Alzheimer's disease: Insight into the role of oxidative stressPROTEOMICS - CLINICAL APPLICATIONS, Issue 5 2008Rukhsana Sultana Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disease. AD is characterized by the presence of senile plaques, neurofibrillary tangles, and synaptic loss. Amyloid ,-peptide (A,), a component of senile plaques, has been proposed to play an important role in oxidative stress in AD brain and could be one of the key factors in the pathogenesis of AD. In the present review, we discuss some of the AD animal models that express A,, and compare the proteomics-identified oxidatively modified proteins between AD brain and those of A, models. Such a comparison would allow better understanding of the role of A, in AD pathogenesis thereby helping in developing potential therapeutics to treat or delay AD. [source] Reductions in N-acetylaspartylglutamate and the 67 kDa form of glutamic acid decarboxylase immunoreactivities in the visual system of albino and pigmented rats after optic nerve transectionsTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 3 2003John R. Moffett Abstract This study compares the immunohistochemical distributions of N-acetylaspartylglutamate (NAAG) and the large isoform of the ,-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase (GAD67) in the visual system of albino and pigmented rats. Most retinal ganglion cells and their axons were strongly immunoreactive for NAAG, whereas GAD67 immunoreactivity was very sparse in these cells and projections. In retinorecipient zones, NAAG and GAD67 immunoreactivities occurred in distinct populations of neurons and in dense networks of strongly immunoreactive fibers and synapses. Dual-labeling immunohistochemistry indicated that principal neurons were stained for NAAG, whereas local interneurons were stained for GAD67. In contrast to the distribution observed in retinorecipient zones, most or all neurons were doubly stained for NAAG and GAD67 in the thalamic reticular nucleus. Ten days after unilateral optic nerve transection, NAAG-immunoreactive fibers and synapses were substantially reduced in all contralateral retinal terminal zones. The posttransection pattern of NAAG-immunoreactive synaptic loss demarcated the contralateral and ipsilateral divisions of the retinal projections. In addition, an apparent transynaptic reduction in GAD67 immunoreactivity was observed in some deafferented areas, such as the lateral geniculate. These findings suggest a complicated picture in which NAAG and GABA are segregated in distinct neuronal populations in primary visual targets, yet they are colocalized in neurons of the thalamic reticular nucleus. This is consistent with NAAG acting as a neurotransmitter release modulator that is coreleased with a variety of classical transmitters in specific neural pathways. J. Comp. Neurol. 458:221,239, 2003. © 2003 Wiley-Liss, Inc. [source] Promotion of axonal maturation and prevention of memory loss in mice by extracts of Astragalus mongholicusBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2006C Tohda Background and purpose: Neurons with atrophic neurites may remain alive and therefore may have the potential to regenerate even when neuronal death has occurred in some parts of the brain. This study aimed to explore effects of drugs that can facilitate the regeneration of neurites and the reconstruction of synapses even in severely damaged neurons. Experimental approach: We investigated the effects of extracts of Astragalus mongholicus on the cognitive defect in mice caused by injection with the amyloid peptide A,(25-35). We also examined the effect of the extract on the regeneration of neurites and the reconstruction of synapses in cultured neurons damaged by A,(25-35). Key results: A. mongholicus extract (1 g kg,1 day,1 for 15 days, p.o.) reversed A,(25-35)-induced memory loss and prevented the loss of axons and synapses in the cerebral cortex and hippocampus in mice. Treatment with A,(25-35) (10 ,M) induced axonal atrophy and synaptic loss in cultured rat cortical neurons. Subsequent treatment with A. mongholicus extract (100 ,g/ml) resulted in significant axonal regeneration, reconstruction of neuronal synapses, and prevention of A,(25-35)-induced neuronal death. Similar extracts of A. membranaceus had no effect on axonal atrophy, synaptic loss, or neuronal death. The major known components of the extracts (astragalosides I, II, and IV) reduced neurodegeneration, but the activity of the extracts did not correlate with their content of these three astragalosides. Conclusion and implications: A. mongholicus is an important candidate for the treatment of memory disorders and the main active constituents may not be the known astragalosides. British Journal of Pharmacology (2006) 149, 532,541. doi:10.1038/sj.bjp.0706865 [source] | |||||||||||||