http://www.molecularneurodegeneration.com The most accessed research articles published by Molecular Neurodegeneration 2010-02-09T00:00:00Z This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ Background: Recent reports suggest that latrepirdine (Dimebon™, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ) peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems. Results: We evaluated extracellular levels of Aβ in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 μM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 μM or 10 μM). Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of Aβ in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 μM) and led to more modest increases in extracellular Aβx-42 levels (+10%; p = 0.001); of note, however, was the observation that extracellular Aβx-40 levels did not change. Conclusions: Here, we report the surprising association of acute latrepirdine dosing with elevated levels of extracellular Aβ as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic latrepirdine treatment with improvement in cognitive function, the effects of chronic latrepirdine treatment on extracellular Aβ levels must now be determined. http://www.molecularneurodegeneration.com/content/4/1/51 John Steele Soong Ho Kim John Cirrito Deborah Verges Jessica Restivo David Westaway Paul Fraser Peter St George Hyslop Mary Sano Ilya Bezprozvanny Michelle Ehrlich David Holtzman Sam Gandy Molecular Neurodegeneration 2009, 4:51 2009-12-17T00:00:00Z doi:10.1186/1750-1326-4-51 Molecular Neurodegeneration 1750-1326 4 51 2009-12-17T00:00:00Z XML The amyloid precursor protein (APP) takes a central position in Alzheimer's disease (AD) pathogenesis: APP processing generates the β-amyloid (Aβ) peptides, which are deposited as the amyloid plaques in brains of AD individuals; Point mutations and duplications of APP are causal for a subset of early onset of familial Alzheimer's disease (FAD). Not surprisingly, the production and pathogenic effect of Aβ has been the central focus in AD field. Nevertheless, the biological properties of APP have also been the subject of intense investigation since its identification nearly 20 years ago as it demonstrates a number of interesting putative physiological roles. Several attractive models of APP function have been put forward recently based on in vitro biochemical studies. Genetic analyses of gain- and loss-of-function mutants in Drosophila and mouse have also revealed important insights into its biological activities in vivo. This article will review the current understanding of APP physiological functions. http://www.molecularneurodegeneration.com/content/1/1/5 Hui Zheng Edward Koo Molecular Neurodegeneration 2006, 1:5 2006-07-03T00:00:00Z doi:10.1186/1750-1326-1-5 Molecular Neurodegeneration 1750-1326 1 5 2006-07-03T00:00:00Z XML Background: Alpha-synuclein is a presynaptic protein with a proposed role in neurotransmission and dopamine homeostasis. Abnormal accumulation of α-synuclein aggregates in dopaminergic neurons of the substantia nigra is diagnostic of sporadic Parkinson's disease, and mutations in the protein are linked to early onset forms of the disease. The folded conformation of the protein varies depending upon its environment and other factors that are poorly understood. When bound to phospholipid membranes, α-synuclein adopts a helical conformation that mediates specific interactions with other proteins. Results: To investigate the role of the helical domain in transport and localization of α-synuclein, eGFP-tagged constructs were transfected into rat primary hippocampal neurons at 7 DIV. A series of constructs were analyzed in which each individual exon was deleted, for comparison to previous studies of lipid affinity and α-helix content. A53T and A30P substitutions, representing Parkinson's disease-associated variants, were analyzed as well. Single exon deletions within the lipid-binding N-terminal domain of α-synuclein (exons 2, 3, and 4) partially disrupted its presynaptic localization at 17-21 DIV, resulting in increased diffuse labeling of axons. Similar results were obtained for A30P, which exhibits decreased lipid binding, but not A53T. To examine whether differences in presynaptic enrichment were related to deficiencies in transport velocity, transport was visualized via live cell microscopy. Tagged α-synuclein migrated at a rate of 1.85 ± 0.09 μm/s, consistent with previous reports, and single exon deletion mutants migrated at similar rates, as did A30P. Deletion of the entire N-terminal lipid-binding domain (Δ234GFP) did not significantly alter rates of particle movement, but decreased the number of moving particles. Only the A53TGFP mutant exhibited a significant decrease in transport velocity as compared to ASGFP. Conclusions: These results support the hypothesis that presynaptic localization involves a mechanism that requires helical conformation and lipid binding. Conversely, the rate of axonal transport is not determined by lipid affinity and is not sufficient to account for differences in presynaptic localization of α-synuclein-eGFP variants. http://www.molecularneurodegeneration.com/content/5/1/9 Mong-Lin Yang Linda Hasadsri Wendy Woods Julia George Molecular Neurodegeneration 2010, 5:9 2010-02-09T00:00:00Z doi:10.1186/1750-1326-5-9 Molecular Neurodegeneration 1750-1326 5 9 2010-02-09T00:00:00Z XML Background: Recent evidence suggests that glycogen synthase kinase-3β (GSK3β) is implicated in both sporadic and familial forms of Alzheimer's disease. The transcription factor, p53 also plays a role and has been linked to an increase in tau hyperphosphorylation although the effect is indirect. There is also evidence that GSK3β and p53 interact and that the activity of both proteins is increased as a result of this interaction. Under normal cellular conditions, p53 is kept at low levels by Mdm2 but when cells are stressed, p53 is stabilised and may then interact with GSK3β. We propose that this interaction has an important contribution to cellular outcomes and to test this hypothesis we developed a stochastic simulation model. Results: The model predicts that high levels of DNA damage leads to increased activity of p53 and GSK3β and low levels of aggregation but if DNA damage is repaired, the aggregates are eventually cleared. The model also shows that over long periods of time, aggregates may start to form due to stochastic events leading to increased levels of ROS and damaged DNA. This is followed by increased activity of p53 and GSK3β and a vicious cycle ensues. Conclusions: Since p53 and GSK3β are both involved in the apoptotic pathway, and GSK3β overactivity leads to increased levels of plaques and tangles, our model might explain the link between protein aggregation and neuronal loss in neurodegeneration. http://www.molecularneurodegeneration.com/content/5/1/7 Carole Proctor Douglas Gray Molecular Neurodegeneration 2010, 5:7 2010-01-26T00:00:00Z doi:10.1186/1750-1326-5-7 Molecular Neurodegeneration 1750-1326 5 7 2010-01-26T00:00:00Z XML α-Synuclein is a small protein that has special relevance for understanding Parkinson disease and related disorders. Not only is α-synuclein found in Lewy bodies characteristic of Parkinson disease, but also mutations in the gene for α-synuclein can cause an inherited form of Parkinson disease and expression of normal α-synuclein can increase the risk of developing Parkinson disease in sporadic, or non-familial, cases. Both sporadic and familial Parkinson disease are characterized by substantial loss of several groups of neurons, including the dopaminergic cells of the substantia nigra that are the target of most current symptomatic therapies. Therefore, it is predicted that α-synuclein, especially in its mutant forms or under conditions where its expression levels are increased, is a toxic protein in the sense that it is associated with an increased rate of neuronal cell death. This review will discuss the experimental contexts in which α-synuclein has been demonstrated to be toxic. I will also outline what is known about the mechanisms by which α-synuclein triggers neuronal damage, and identify some of the current gaps in our knowledge about this subject. Finally, the therapeutic implications of toxicity of α-synuclein will be discussed. http://www.molecularneurodegeneration.com/content/4/1/9 Mark Cookson Molecular Neurodegeneration 2009, 4:9 2009-02-04T00:00:00Z doi:10.1186/1750-1326-4-9 Molecular Neurodegeneration 1750-1326 4 9 2009-02-04T00:00:00Z XML The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state. http://www.molecularneurodegeneration.com/content/2/1/22 Sarah Cole Robert Vassar Molecular Neurodegeneration 2007, 2:22 2007-11-15T00:00:00Z doi:10.1186/1750-1326-2-22 Molecular Neurodegeneration 1750-1326 2 22 2007-11-15T00:00:00Z XML Autophagy is the major pathway involved in the degradation of proteins and organelles, cellular remodeling, and survival during nutrient starvation. Autophagosomal dysfunction has been implicated in an increasing number of diseases from cancer to bacterial and viral infections and more recently in neurodegeneration. While a decrease in autophagic activity appears to interfere with protein degradation and possibly organelle turnover, increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models. On the other hand, too much autophagic activity can be detrimental as well and lead to cell death, suggesting the regulation of autophagy has an important role in cell fate decisions. An increasing number of model systems are now available to study the role of autophagy in the central nervous system and how it might be exploited to treat disease. We will review here the current knowledge of autophagy in the central nervous system and provide an overview of the various models that have been used to study acute and chronic neurodegeneration. http://www.molecularneurodegeneration.com/content/4/1/16 Philipp Jaeger Tony Wyss-Coray Molecular Neurodegeneration 2009, 4:16 2009-04-06T00:00:00Z doi:10.1186/1750-1326-4-16 Molecular Neurodegeneration 1750-1326 4 16 2009-04-06T00:00:00Z XML Prion diseases are disorders of protein conformation in which PrPC, the normal cellular conformer, is converted to an abnormal, protease-resistant conformer rPrPSc. Approximately 80% of rPrPSc accumulates in neuronal plasma membranes where it changes their physical properties and profoundly affects membrane functions. In this review we explain how rPrPSc is transported along axons to presynaptic boutons and how we envision the conversion of PrPC to rPrPSc in the postsynaptic membrane. This information is a prerequisite to the second half of this review in which we present evidence that rPrPSc accumulation in synaptic regions links Notch-1 signaling with the dendritic degeneration. The hypothesis that the Notch-1 intracellular domain, NICD, is involved in prion disease was tested by treating prion-infected mice with the γ-secretase inhibitor (GSI) LY411575, with quinacrine (Qa), and with the combination of GSI + Qa. Surprisingly, treatment with GSI alone markedly decreased NICD but did not prevent dendritic degeneration. Qa alone produced near normal dendritic trees. The combined GSI + Qa treatment resulted in a richer dendritic tree than in controls. We speculate that treatment with GSI alone inhibited both stimulators and inhibitors of dendritic growth. With the combined GSI + Qa treatment, Qa modulated the effect of GSI perhaps by destabilizing membrane rafts. GSI + Qa decreased PrPSc in the neocortex and the hippocampus by 95%, but only by 50% in the thalamus where disease was begun by intrathalamic inoculation of prions. The results of this study indicate that GSI + Qa work synergistically to prevent dendrite degeneration and to block formation of PrPSc. http://www.molecularneurodegeneration.com/content/5/1/6 Stephen DeArmond Krystyna Bajsarowicz Molecular Neurodegeneration 2010, 5:6 2010-01-21T00:00:00Z doi:10.1186/1750-1326-5-6 Molecular Neurodegeneration 1750-1326 5 6 2010-01-21T00:00:00Z XML The presence of amyloid-β (Aβ) deposits in selected brain regions is a hallmark of Alzheimer's disease (AD). The amyloid deposits have "chaperone molecules" which play critical roles in amyloid formation and toxicity. We report here that treatment of rat hippocampal neurons with Aβ-acetylcholinesterase (Aβ-AChE) complexes induced neurite network dystrophia and apoptosis. Moreover, the Aβ-AChE complexes induced a sustained increase in intracellular Ca2+ as well as a loss of mitochondrial membrane potential. The Aβ-AChE oligomers complex also induced higher alteration of Ca2+ homeostasis compared with Aβ-AChE fibrillar complexes. These alterations in calcium homeostasis were reversed when the neurons were treated previously with lithium, a GSK-3β inhibitor; Wnt-7a ligand, an activator for Wnt Pathway; and an N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801), demonstrating protective roles for activation of the Wnt signaling pathway as well as for NMDA-receptor inhibition. Our results indicate that the Aβ-AChE complexes enhance Aβ-dependent deregulation of intracellular Ca2+ as well as mitochondrial dysfunction in hippocampal neurons, triggering an enhanced damage than Aβ alone. From a therapeutic point of view, activation of the Wnt signaling pathway, as well as NMDAR inhibition may be important factors to protect neurons under Aβ-AChE attack. http://www.molecularneurodegeneration.com/content/5/1/4 Margarita Dinamarca Juan Sagal Rodrigo Quintanilla Juan Godoy Macarena Arrazola Nibaldo Inestrosa Molecular Neurodegeneration 2010, 5:4 2010-01-18T00:00:00Z doi:10.1186/1750-1326-5-4 Molecular Neurodegeneration 1750-1326 5 4 2010-01-18T00:00:00Z XML ObjectiveAlzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD. Methods: From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate); (3) high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate); or (4) high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat). At age 18 wks, mice were sacrificed, and brains studied for (a) wet weight; (b) solubilizable Aβ content by ELISA; (c) amyloid plaque burden; (d) stereologic analysis of selected hippocampal subregions. Results: Animals receiving a high fat diet showed increased brain levels of solubilizable Aβ, although we detected no effect on plaque burden. Unexpectedly, brains of mice fed a high protein/low carbohydrate diet were 5% lower in weight than brains from all other mice. In an effort to identify regions that might link loss of brain mass to cognitive function, we studied neuronal density and volume in hippocampal subregions. Neuronal density and volume in the hippocampal CA3 region of TgCRND8 mice tended to be lower in TgCRND8 mice receiving the high protein/low carbohydrate diet than in those receiving the regular chow. Neuronal density and volume were preserved in CA1 and in the dentate gyrus.InterpretationDissociation of Aβ changes from brain mass changes raises the possibility that diet plays a role not only in modulating amyloidosis but also in modulating neuronal vulnerability. However, in the absence of a study of the effects of a high protein/low carbohydrate diet on nontransgenic mice, one cannot be certain how much, if any, of the loss of brain mass exhibited by high protein/low carbohydrate diet-fed TgCRND8 mice was due to an interaction between cerebral amyloidosis and diet. Given the recent evidence that certain factors favor the maintenance of cognitive function in the face of substantial structural neuropathology, we propose that there might also exist factors that sensitize brain neurons to some forms of neurotoxicity, including, perhaps, amyloid neurotoxicity. Identification of these factors could help reconcile the poor clinicopathological correlation between cognitive status and structural neuropathology, including amyloid pathology. http://www.molecularneurodegeneration.com/content/4/1/40 Steve Pedrini Carlos Thomas Hannah Brautigam James Schmeidler Lap Ho Paul Fraser David Westaway Peter St George Hyslop Ralph Martins Joseph Buxbaum Giulio Pasinetti Dara Dickstein Patrick Hof Michelle Ehrlich Sam Gandy Molecular Neurodegeneration 2009, 4:40 2009-10-21T00:00:00Z doi:10.1186/1750-1326-4-40 Molecular Neurodegeneration 1750-1326 4 40 2009-10-21T00:00:00Z XML