Behav Brain Res. 2011 Jan 1;216(1):408-13. Epub 2010 Sep 8.
Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein (APP) mice.
Emotional Brain Institute, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, United States; Departments of Child & Adolescent Psychiatry, New York University School of Medicine, New York, NY 10016, United States.
Abstract
Elucidating the modulators of social behavioral is important in understanding the neural basis of behavior and in developing methods to enhance behavior in cases of disorder. The work here stems from the observation that the Alzheimer's disease mouse model Tg2576, overexpressing human mutations of the amyloid-β precursor protein (APP), fails to construct nests when supplied paper towels in their home cages. Experiments using commercially available cotton nesting material found similar results. Additional experiments revealed that the genotype effect is progressively modulated by age in APP mice but not their WT counterparts. There was no effect of sex on nesting behavior in any group. Finally, this effect was independent of ambient temperature - even when subjected to a cold environment, APP mice fail to build nests whereas WT mice do. These results suggest that the APP gene plays a role in affiliative behaviors and are discussed in relation to disorders characteristic of mutations in the APP gene and in affective dysfunction, including Alzheimer's disease.Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20804789 [PubMed - in process]PMCID: PMC2975804 [Available on 2012/1/1]
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2.
Behav Brain Res. 2011 Jan 1;216(1):77-83. Epub 2010 Jul 22.
Increased aggression in males in transgenic Tg2576 mouse model of Alzheimer's disease.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Abstract
Behavioural and psychological signs and symptoms of dementia encompass a wide range of neuropsychiatric disturbances which coincide with progressing cognitive decline in Alzheimer's disease (AD). Physical aggression and agitation, which occurs in 20-65% of AD patients, is physically and emotionally stressful, not only to patients but also to immediate family and caregivers. The exact mechanisms underlying the increased aggressive behaviour in AD has yet to be elucidated. We used a transgenic mouse model, denoted Tg2576, which over-expresses a mutated human amyloid precursor protein (APP) gene implicated in familial AD, to investigate aggressive behaviour of males at the stage of amyloid beta pathology preceding overt amyloid plaque deposition in the brain. The aggressive behaviour of transgenic and non-transgenic littermate males was evaluated in a standard resident-intruder test in which an isolated resident male responded aggressively toward an experimentally naïve intruder male of A/J strain. We showed that 7-month-old Tg2576 resident males demonstrated significantly higher and unchanged level of aggression towards intruder males during 3 consecutive encounters as compared to their non-transgenic littermate counterparts. These results validate further the Tg2576 mouse model of AD underscoring its usefulness in studying non-mnemonic changes in behaviour related to the disease.Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20655336 [PubMed - in process]
Related citations 3.
J Neurosci Res. 2011 Jan;89(1):22-28.
The case for blood-brain barrier dysfunction in the pathogenesis of Alzheimer's disease.
Faculty of Applied Health Sciences, Brock University, St. Catharine's, Ontario, Canada.
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that leads to a progressive loss of integrative and memory capacities of the brain. This is the predominant form of neurodegenerative dementia, with a growing prevalence of between 1 in 50 and 1 in 100 in North America. Numerous hypotheses related to the etiology of AD have developed over the years. However, among the various published hypotheses, the predominant one is related to the progressive and prominent accumulation of central nervous system β-amyloid peptide and the ensuing brain burden created. It is, therefore, important to consider the homeostatic mechanisms underlying β-amyloid transport dynamics between the brain and blood vascular compartments. As well, there is a dynamic interrelationship between soluble and insoluble forms of the peptide. Factors that underlie and regulate these dynamic processes are likely relevant to the end accumulation of β-amyloid peptide in the brain compartment and ultimately in insoluble forms, which is characteristic of, and significant for, the pathophysiology of the Alzheimer's brain. Significantly, and in particular relation to the amyloid burden theory mentioned above, it has been postulated that a dysfunctioning blood-brain barrier (BBB) may play a significant, if not critical, role in the pathogenesis of AD. By allowing the influx of injurious materials or agents into the brain or by impeding or blocking the efflux of those materials and/or agents, BBB-related neuronopathies and their associated sequelae could, and do, ensue. © 2010 Wiley-Liss, Inc.PMID: 21046564 [PubMed - as supplied by publisher]
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4.
Methods Mol Biol. 2011;670:141-53.
Aβ toxicity in primary cultured neurons.
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Abstract
The aggregation of beta-amyloid (Aβ) into soluble oligomers is considered an early event in Alzheimer's disease. Furthermore, the presence of these aggregates seems to lead to neurodegeneration in the context of this disease. However, the mechanisms underlying Aβ-induced neurotoxicity are not completely understood. Primary cultures of pyramidal neurons have proven to be an excellent model system for the study of such mechanisms. These cultures provide a homogenous population of neurons that extend and differentiate axons and dendrites and that establish functional synapses among them. In addition, the neurotoxic effects of preaggregated Aβ can be easily analyzed both morphologically and biochemically. Here, we describe in detail the materials and methods used for the preparation and maintenance of primary cultures of hippocampal pyramidal neurons, as well as for the aggregation of and treatment with Aβ.PMID: 20967589 [PubMed - in process]
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5.
Methods Mol Biol. 2011;670:71-84.
Measuring APP carboxy-terminal fragments.
ProteoTech, Inc, Kirkland, WA, USA. esposito@proteotech.com
Abstract
The accumulation of the amyloid-β (Aβ) peptide in the form of insoluble fibrillar deposits and soluble oligomeric aggregates is widely believed to play a causal role in Alzheimer's disease (AD). Proteolytic cleavage of APP by the β-site APP cleaving enzyme (BACE1) near the C-terminus results in the formation of the APP C-terminal fragment (CTF) C99, a substrate for subsequent cleavage by γ-secretase to generate Aβ. Alternatively, APP cleavage by α-secretase to generate the APP CTF C83 occurs within the Aβ region, precluding its formation. Therefore, modulation of β- and/or γ-secretase activity represents important therapeutic targets. Transgenic mice overexpressing human APP generate detectable levels of APP CTFs and Aβ. We have shown that highly sensitive and specific methods for determining levels of APP CTFs and Aβ are useful for understanding how genetic manipulation of APP processing impacts Aβ generation and accumulation.PMID: 20967584 [PubMed - in process]
Related citations 6.
Methods Mol Biol. 2011;670:57-70.
Assessing Aβ aggregation state by atomic force microscopy.
The C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV, USA.
Abstract
There has been a growing recognition of a wide variety of diseases commonly referred to as conformational diseases, which share the feature of specific disease-related proteins adopting nonnative conformation that promote their ordered aggregation and deposition on surfaces. Due to the nanoscale dimensions and the varied morphology of such aggregates, atomic force microscopy (AFM) has emerged as an ideal tool for distinguishing structural features of the numerous potential aggregate forms, ranging from small globular oligomers to large mature amyloid fibrils. Beyond the ability to morphologically distinguish aggregate forms, AFM also can dynamically track the aggregation process due to its unique ability to be operated not only in air (ex situ), but also in solution (in situ). This feature provides for tracking the fate of individual aggregates over time. This chapter describes the use of AFM in characterizing the aggregation of the amyloid-β peptide (Aβ), which is hypothesized to play a key role in Alzheimer's disease (AD), a late-onset neurodegenerative conformational disease.PMID: 20967583 [PubMed - in process]
Related citations 7.
Methods Mol Biol. 2011;670:45-56.
Detecting aβ*56 oligomers in brain tissues.
Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA.
Abstract
Since its original description in 1906 by Dr Alois Alzheimer, amyloid plaques and neurofibrillary tangles have remained the hypothetical cause of Alzheimer's disease. However, plaque burden poorly predicts cognitive status in humans, which led several groups to investigate the possibility that soluble species of amyloid-beta (Aβ) peptides could be playing an important pathological function in the aging brain. Through a multistep fractionation protocol, we identified a 56 kDa oligomer of Aβ, termed Aβ*56, the amount of which correlates with cognitive impairment. Here, we describe our biochemical approach to isolate this oligomeric Aβ species in brain tissue of transgenic mouse models of AD.PMID: 20967582 [PubMed - in process]
Related citations 8.
Methods Mol Biol. 2011;670:33-44.
Isolation of low-n amyloid β-protein oligomers from cultured cells, CSF, and brain.
Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
Abstract
Recent data suggest that soluble, non-fibrillar assemblies of the amyloid β-protein (Aβ) may mediate the synaptic deficits that characterize the early stages of Alzheimer's disease. Consequently, much effort has been expended in isolating and studying a variety of different Aβ assemblies. Here, we describe the use of immunoprecipitation/western blotting and size exclusion chromatography/western blotting to characterize Aβ present in conditioned medium from cultured cells, human cerebrospinal fluid, and human cortex extracted with aqueous buffer, detergent, and formic acid.PMID: 20967581 [PubMed - in process]
Related citations 9.
Methods Mol Biol. 2011;670:13-32.
Preparing synthetic Aβ in different aggregation states.
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
Abstract
This chapter outlines protocols that produce homogenous preparations of oligomeric and fibrillar amyloid-β peptide (Aβ). While there are several isoforms of this peptide, the 42 amino acid form is the focus because of its genetic and pathological link to Alzheimer's disease (AD). Past decades of AD research highlight the dependence of Aβ42 function on its structural assembly state. Biochemical, cellular and in vivo studies of Aβ42 usually begin with purified peptide obtained by chemical synthesis or recombinant expression. The initial steps to solubilize and prepare these purified dry peptide stocks are critical to controlling the structural assembly of Aβ. To develop homogenous Aβ42 assemblies, we initially monomerize the peptide, erasing any "structural history" that could seed aggregation, by using a strong solvent. It is this starting material that has allowed us to define and optimize conditions that consistently produce homogenous solutions of soluble oligomeric and fibrillar Aβ42 assemblies. These preparations have been developed and characterized by using atomic force microscopy (AFM) to identify the structurally discrete species formed by Aβ42 under specific solution conditions. These preparations have been used extensively to demonstrate a variety of functional differences between oligomeric and fibrillar Aβ42. We also present a protocol for fluorescently labeling oligomeric Aβ42 that does not affect structure, as measured by AFM, or function, as measured by a cellular uptake assay. These reagents are critical experimental tools that allow for defining specific structure/function connections.PMID: 20967580 [PubMed - in process]
Related citations 10.
Neurobiol Dis. 2011 Jan;41(1):62-70. Epub 2010 Sep 9.
L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease.
Department of Neurology, Oregon Health & Science University, Portland, OR, USA; Portland Veteran Administration Medical Center, Oregon Health & Science University, Portland, OR, USA.
Abstract
There is strong evidence that intracellular calcium dysregulation plays an important pathological role in Alzheimer's disease, and specifically that beta amyloid may induce increases in intracellular calcium and lead to neuronal cell dysfunction and death. Here we investigated the feasibility of modifying Alzheimer's pathology with the L-type voltage-gated calcium channel blockers verapamil, diltiazem, isradipine and nimodipine. All four compounds protected MC65 neuroblastoma cells from amyloid beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity. Isradipine was the most potent blocker, preventing APP CTF neurotoxicity at nanomolar concentrations. Intracellular beta amyloid expression was associated with increased expression of Cav 1.2 calcium channels and increased intracellular calcium influx from the extracellular space. Despite the cytoprotection afforded by calcium channel blockers, amyloid beta oligomer formation was not suppressed. The mechanism of cell death in MC65 cells is appeared to be caspase-3 independent. With the goal of determining if there is sufficient experimental support to move forward with animal trials of isradipine, we determined its bioavailability in the triple transgenic mouse model of AD. Subcutaneous implantation of carrier-bound isradipine (3μg/g/day) for 60days resulted in nanomolar concentrations in both the plasma and brain. Taken together, our in vitro results support the theory that calcium blockers exert protective effects downstream of the effects of beta amyloid. Isradipine's neuroprotective effect at concentrations that are clinically relevant and achievable in vitro and in vivo suggests that this particular calcium blocking agent may have therapeutic value in the treatment of Alzheimer's disease.Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 20816785 [PubMed - in process]PMCID: PMC2982927 [Available on 2012/1/1]
Related citations 11.
Eur J Pharmacol. 2010 Dec 15;649(1-3):195-201. Epub 2010 Sep 22.
Puerarin attenuates amyloid-beta-induced cognitive impairment through suppression of apoptosis in rat hippocampus in vivo.
The Institute of Medicine, Qiqihar Medical University, Qiqihar 161006, China.
Abstract
Elevated levels of β-amyloid (Aβ) in the brains being a hallmark of Alzheimer's disease have been believed to play a critical role in the cognitive dysfunction that occurs in Alzheimer's disease. Recent evidence suggests that Aβ induces neuronal apoptosis in the brain and in primary neuronal cultures. In this study, we investigated the effects of puerarin, a phytoestrogen isolated from Pueraria lobata, on cognitive function and neuronal apoptosis in the intrahippocampal injection of Aβ rats and its mechanism of action. The results show the intrahippocampal injection of Aβ induced a spatial memory deficit, apoptosis, and caspase-9 activation in hippocampal neurons. Puerarin treatment ameliorated Aβ(1-42)-induced cognitive impairment and reversed the increase of apoptosis in the hippocampus. The attenuation is associated with the activation of Akt and phosphorylation of Bad. These results suggest that puerarin may be an anti-Alzheimer's disease candidate drug to suppress both Alzheimer's disease-related neuronal cell apoptosis and dysfunction of the memory system.Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20868658 [PubMed - in process]
Related citations 12.
Neuroscience. 2010 Dec 15;171(3):859-868. Epub 2010 Sep 25.
Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced oxidative and inflammatory responses in astrocytes.
Department of Biological Engineering, University of Missouri, Columbia, MO 65211, USA.
Abstract
Oxidative stress and inflammation are important processes in the progression of Alzheimer's disease (AD). Recent studies have implicated the role of amyloid β-peptides (Aβ) in mediating these processes. In astrocytes, oligomeric Aβ induces the assembly of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes resulting in its activation to produce anionic superoxide. Aβ also promotes production of pro-inflammatory factors in astrocytes. Since low energy laser has previously been reported to attenuate oxidative stress and inflammation in biological systems, the objective of this study was to examine whether this type of laser light was able to abrogate the oxidative and inflammatory responses induced by Aβ. Primary rat astrocytes were exposed to Helium-Neon laser (λ=632.8 nm), followed by the treatment with oligomeric Aβ. Primary rat astrocytes were used to measure Aβ-induced production of superoxide anions using fluorescence microscopy of dihydroethidium (DHE), assembly of NADPH oxidase subunits by the colocalization between the cytosolic p47(phox) subunit and the membrane gp91(phox) subunit using fluorescent confocal microscopy, phosphorylation of cytosolic phospholipase A(2) cPLA(2) and expressions of pro-inflammatory factors including interleukin-1β (IL-1β) and inducible nitric-oxide synthase (iNOS) using Western blot Analysis. Our data showed that laser light at 632.8 nm suppressed Aβ-induced superoxide production, colocalization between NADPH oxidase gp91(phox) and p47(phox) subunits, phosphorylation of cPLA(2,) and the expressions of IL-1β and iNOS in primary astrocytes. We demonstrated for the first time that 632.8 nm laser was capable of suppressing cellular pathways of oxidative stress and inflammatory responses critical in the pathogenesis in AD. This study should prove to provide the groundwork for further investigations for the potential use of laser therapy as a treatment for AD.Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
PMID: 20884337 [PubMed - as supplied by publisher]PMCID: PMC2987533 [Available on 2011/12/1]
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13.
Nitric Oxide. 2010 Dec 15;23(4):289-99. Epub 2010 Sep 4.
Adaptation to intermittent hypoxia restricts nitric oxide overproduction and prevents beta-amyloid toxicity in rat brain.
Goryacheva AV, Kruglov SV, Pshennikova MG, Smirin BV, Malyshev IY, Barskov IV, Viktorov IV, Downey HF, Manukhina EB.
Institute of General Pathology and Pathophysiology, Baltijskaya 8, Moscow 125315, Russia.
Abstract
This study tested the hypothesis that adaptation to intermittent hypoxia (AIH) can prevent overproduction of nitric oxide (NO) in brain and neurodegeneration induced by beta-amyloid (Aβ) toxicity. Rats were injected with a Aβ protein fragment (25-35) into the nucleus basalis magnocellularis. AIH (simulated altitude of 4000 m, 14 days, 4h daily) was produced prior to the Aβ injection. A passive, shock-avoidance, conditioned response test was used to evaluate memory function. Degenerating neurons were visualized in stained cortical sections. NO production was evaluated in brain tissue by the content of nitrite and nitrate. Expression of nNOS, iNOS, and eNOS was measured in the cortex and the hippocampus using Western blot analysis. 3-Nitrotyrosine formation, a marker of protein nitration, was quantified by slot blot analysis. Aβ injection impaired memory of rats; AIH significantly alleviated this disorder. Histological examination confirmed the protective effect of AIH. Degenerating neurons, which were numerous in the cortex of Aβ-injected, unadapted rats, were essentially absent in the brain of hypoxia-adapted rats. Injections of Aβ resulted in significant increases in NOx and in expression of all NOS isoforms in brain; AIH blunted these increases. NO overproduction was associated with increased amounts of 3-nitrotyrosine in the cortex and hippocampus. AIH alone did not significantly influence tissue 3-nitrotyrosine, but significantly restricted its increase after the Aβ injection. Therefore, AIH affords significant protection against experimental Alzheimer's disease, and this protection correlates with restricted NO overproduction.Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 20804853 [PubMed - in process]
Related citations 14.
Neurosci Lett. 2010 Dec 10;486(2):68-72. Epub 2010 Sep 15.
Alzheimer's secretases regulate voltage-gated sodium channels.
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Abstract
BACE1 and presenilin (PS)/γ-secretase are primary proteolytic enzymes responsible for the generation of pathogenic amyloid β-peptides (Aβ) in Alzheimer's disease. We and others have found that β-subunits of the voltage-gated sodium channel (Na(v)βs) also undergo sequential proteolytic cleavages mediated by BACE1 and PS/γ-secretase. In a follow-up study, we reported that elevated BACE1 activity regulates total and surface expression of voltage-gated sodium channels (Na(v)1 channels) and thereby modulates sodium currents in neuronal cells and mouse brains. In this review, we focus on the molecular mechanism of how BACE1 and PS/γ-secretase regulate Na(v)1 channels in neuronal cells. We will also discuss potential physiological and pathological roles of BACE1- and PS/γ-secretase-mediated processing of Na(v)βs in relation to Na(v)1 channel function.Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
PMID: 20817076 [PubMed - in process]PMCID: PMC2964382 [Available on 2011/12/1]
Related citations 15.
Mol Biosyst. 2010 Dec 8;6(12):2389-91. Epub 2010 Oct 7.
Rapid and efficient screening of Alzheimer's disease β-amyloid inhibitors using label-free gold nanoparticles.
Laboratory of Chemical Biology, Division of Biological Inorganic Chemistry, State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China. xqu@ciac.jl.cn.
Abstract
Herein we report that a visual, label-free gold nanoparticle-based assay for rapid and efficient screening of Alzheimer's disease β-amyloid inhibitors.PMID: 20931124 [PubMed - in process]
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16.
Neuroreport. 2010 Dec 8;21(17):1121-5.
Localization of HtrA2/Omi immunoreactivity in brains affected by Alzheimer's disease.
Department of Neurology, Faculty of Medicine, Kyoto University, Sakyoku, Kyoto, Japan. kawamoto@kuhp.kyoto-u.ac.jp
Abstract
HtrA2/Omi is a mitochondrial serine protease that promotes apoptotic processes, and this study investigated whether the abnormal immunoexpression of HtrA2/Omi occurs in patients with Alzheimer's disease. We prepared autopsied brains from seven control individuals and seven patients with Alzheimer's disease, and then carried out immunohistochemical studies on HtrA2/Omi using formalin-fixed, paraffin-embedded sections from all of these cases. In the cerebral cortex and hippocampus from the cases of Alzheimer's disease, densely accumulated HtrA2/Omi immunoreactivity was scattered, both intracellularly and extracellularly. Double immunofluorescence analyses showed the partial localization of HtrA2/Omi immunoreactivity in amyloid β-peptide-immunopositive senile plaques and phosphorylated τ-immunopositive neurofibrillary tangles. These results suggest that HtrA2/Omi may be partially associated with the pathogenesis of Alzheimer's disease.PMID: 20938363 [PubMed - in process]
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17.
J Mol Biol. 2010 Dec 3;404(3):537-52. Epub 2010 Oct 1.
Mechanism of fiber assembly: treatment of aβ Peptide aggregation with a coarse-grained United-residue force field.
Department of Physics and Astronomy, Louisiana State University, Baton Rouge, LA 70803, USA; Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301, USA.
Abstract
The growth mechanism of β-amyloid (Aβ) peptide fibrils was studied by a physics-based coarse-grained united-residue model and molecular dynamics (MD) simulations. To identify the mechanism of monomer addition to an Aβ(1-40) fibril, we placed an unstructured monomer at a distance of 20 Å from a fibril template and allowed it to interact freely with the latter. The monomer was not biased towards fibril conformation by either the force field or the MD algorithm. With the use of a coarse-grained model with replica-exchange molecular dynamics, a longer timescale was accessible, making it possible to observe how the monomers probe different binding modes during their search for the fibril conformation. Although different assembly pathways were seen, they all follow a dock-lock mechanism with two distinct locking stages, consistent with experimental data on fibril elongation. Whereas these experiments have not been able to characterize the conformations populating the different stages, we have been able to describe these different stages explicitly by following free monomers as they dock onto a fibril template and to adopt the fibril conformation (i.e., we describe fibril elongation step by step at the molecular level). During the first stage of the assembly ("docking"), the monomer tries different conformations. After docking, the monomer is locked into the fibril through two different locking stages. In the first stage, the monomer forms hydrogen bonds with the fibril template along one of the strands in a two-stranded β-hairpin; in the second stage, hydrogen bonds are formed along the second strand, locking the monomer into the fibril structure. The data reveal a free-energy barrier separating the two locking stages. The importance of hydrophobic interactions and hydrogen bonds in the stability of the Aβ fibril structure was examined by carrying out additional canonical MD simulations of oligomers with different numbers of chains (4-16 chains), with the fibril structure as the initial conformation. The data confirm that the structures are stabilized largely by hydrophobic interactions and show that intermolecular hydrogen bonds are highly stable and contribute to the stability of the oligomers as well.Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID: 20888834 [PubMed - in process]PMCID: PMC2981693 [Available on 2011/12/1]
Related citations 18.
Brain Res. 2010 Dec 2;1363:180-90. Epub 2010 Sep 25.
Altered distribution of mGlu2 receptors in β-amyloid-affected brain regions of Alzheimer cases and aged PS2APP mice.
Abstract
Altered glutamatergic synaptic transmission is among the key events defining the course of Alzheimer's disease (AD). mGlu2 receptors, a subtype of group II metabotropic glutamate receptors, regulate (as autoreceptors) fast synaptic transmission in the CNS via the controlled release of the excitatory amino acid glutamate. Since their pharmacological manipulation in rodents has been reported to affect cognition, they are potential drug targets for AD therapy. We examined the fate of these receptors in cases of AD as well as in aging PS2APP mice-a proposed model of the disease. In vitro binding of [(3)H]LY354740, a selective group II agonist (with selective affinity for mGlu2 receptors, under the assay conditions used) and quantitative radioautography revealed a partial, but highly significant, loss of receptors in amyloid-affected discrete brain regions of AD cases and PS2APP mice. Among the mouse brain regions affected were, above all, the subiculum but also frontolateral cortex, dentate gyrus, lacunosum moleculare and caudate putamen. In AD, significant receptor losses were registered in entorhinal cortex and lacunosum moleculare (40% and 35%, respectively). These findings have implications for the development of selective ligands for symptomatic therapy in AD and for its diagnosis.Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20875805 [PubMed - in process]
Related citations 19.
Acta Diabetol. 2010 Dec;47(4):279-93. Epub 2010 Aug 27.
Encephalopathies: the emerging diabetic complications.
Department of Pathology, Wayne State University, Detroit, MI 48201, USA. asima@med.wayne.edu
Abstract
Diabetic encephalopathies are now accepted complications of diabetes. They appear to differ in type 1 and type 2 diabetes as to underlying mechanisms and the nature of resulting cognitive deficits. The increased incidence of Alzheimer's disease in type 2 diabetes is associated with insulin resistance, hyperinsulinemia and hyperglycemia, and commonly accompanying attributes such as hypercholesterolemia, hypertension and obesity. The relevance of these disorders as to the emergence of dementia and Alzheimer's disease is discussed based on epidemiological studies. The pathobiology of accumulation of β-amyloid and tau the hallmarks of Alzheimer's disease are discussed based on experimental data. Type 1 diabetic encephalopathy is likely to increase as a result of the global increase in the incidence of type 1 diabetes and its occurrence in increasingly younger patients. Alzheimer-like changes and dementia are not prominently increased in type 1 diabetes. Instead, the type 1 diabetic encephalopathy involves learning abilities, intelligence development and memory retrieval resulting in impaired school and professional performances. The major underlying component here appears to be insulin deficiency with downstream effects on the expression of neurotrophic factors, neurotransmitters, oxidative and apoptotic stressors resulting in defects in neuronal integrity, connectivity and loss commonly occurring in the still developing brain. Recent experimental data emphasize the role of impaired central insulin action and provide information as to potential therapies. Therefore, the underlying mechanisms resulting in diabetic encephalopathies are complex and appear to differ between the two types of diabetes. Major headway has been made in our understanding of their pathobiology; however, many questions remain to be clarified. In view of the increasing incidence of both type 1 and type 2 diabetes, intensified investigations are called for to expand our understanding of these complications and to find therapeutic means by which these disastrous consequences can be prevented and modified.PMID: 20798963 [PubMed - in process]
Related citations 20.
Aging Cell. 2010 Dec;9(6):1018-31. doi: 10.1111/j.1474-9726.2010.00632.x. Epub 2010 Oct 29.
SCF(Fbx2) -E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function.
Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA Laboratory of Frontier Science, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan Geriatric Research and Clinical Center, James J. Peters VA Medical Center, Bronx, NY, USA.
Abstract
BACE1 (β-secretase) plays a central role in the β-amyloidogenesis of Alzheimer's disease (AD). The ubiquitin-proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and β-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPARγ coactivator-1α (PGC-1α) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC-1α was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing β-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD.© 2010 The Authors. Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
PMID: 20854419 [PubMed - in process]
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