Neurobiol Dis. 2010 Oct 1. [Epub ahead of print]
17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease.
Massone S, Vassallo I, Fiorino G, Castelnuovo M, Barbieri F, Borghi R, Tabaton M, Robello M, Gatta E, Russo C, Florio T, Dieci G, Cancedda R, Pagano A.
Oncology Biology and Genetics Department (DOBiG), University of Genoa, Genoa, Italy; National Institute for Cancer Research (IST) Genoa, Largo R. Benzi, 10, 16132 Genoa, Italy.
Abstract
Alternative splicing is a central component of human brain complexity; nonetheless, its regulatory mechanisms are still largely unclear. In this work, we describe a novel non-coding (nc) RNA (named 17A) RNA polymerase (pol) III-dependent embedded in the human G-protein-coupled receptor 51 gene (GPR51, GABA B2 receptor). The stable expression of 17A in SHSY5Y neuroblastoma cells induces the synthesis of an alternative splicing isoform that abolish GABA B2 intracellular signaling (i.e., inhibition of cAMP accumulation and activation of K(+) channels). Indeed, 17A is expressed in human brain, and we report that it is upregulated in cerebral tissues derived from Alzheimer disease patients. We demonstrate that 17A expression in neuroblastoma cells enhances the secretion of amyloid β peptide (Aβ) and the Aβ x-42/Αβ x-40 peptide ratio and that its synthesis is induced in response to inflammatory stimuli. These data correlate, for the first time, the activity of a novel pol III-dependent ncRNA to alternative splicing events and, possibly, to neurodegeneration induced by abnormal GABA B function. We anticipate that further analysis of pol III-dependent regulation of alternative splicing will disclose novel regulatory pathways associated to brain physiology and/or pathology.PMID: 20888417 [PubMed - as supplied by publisher]
Related citations
42.
Biochem Biophys Res Commun. 2010 Oct 1. [Epub ahead of print]
Potent inhibitors of amyloid β fibrillization, 4,5-dianilinophthalimide and staurosporine aglycone, enhance degradation of preformed aggregates of mutant Notch3.
Department of Vascular Dementia Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology (NCGG), Aichi, Japan.
Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in human NOTCH3. We have recently reported that mutant Notch3 shows a greater propensity to form aggregates, and these aggregates resist degradation, leading to accumulation in the endoplasmic reticulum (ER). In this study, we searched for low-molecular compounds that decrease the amount of mutant Notch3 aggregates. Using a cell-based system, we found that degradation of preformed mutant aggregates was enhanced by treatment with either 4,5-dianilinophthalimide (DAPH) or staurosporine aglycone (SA), both of which inhibit amyloid β (Aβ) fibrillization. Regarding other low-molecular compounds interacting with Aβ fibrils, thioflavin T (ThT) also enhanced the clearance of mutant Notch3. These findings suggest that DAPH, SA, and ThT are potent reagents to dissociate the preformed aggregates of mutant Notch3 by disruption of intermolecular contacts of misfolded proteins. Our study may provide the basis for the development of a pharmacological therapy for CADASIL.PMID: 20888320 [PubMed - as supplied by publisher]
Related citations 43.
Protein Sci. 2010 Sep 30. [Epub ahead of print]
N-terminal engineering of amyloid-β-binding affibody molecules yields improved chemical synthesis and higher binding affinity.
Lindgren J, Wahlström A, Danielsson J, Markova N, Ekblad C, Gräslund A, Abrahmsén L, Karlström AE, Wärmländer SK.
Royal Institute of Technology (KTH), School of Biotechnology, Division of Molecular Biotechnology, AlbaNova University Centre, 106 91 Stockholm, Sweden.
Abstract
The aggregation of amyloid-β (Aβ) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease. Molecules binding with high affinity and selectivity to Aβ-peptides are important tools for investigating the aggregation process. An Aβ-binding Affibody molecule, Z(Aβ3), has earlier been selected by phage display and shown to bind Aβ(1-40) with nanomolar affinity and to inhibit Aβ-peptide aggregation. In this study we create truncated functional versions of the Z(Aβ3) Affibody molecule better suited for chemical synthesis production. Engineered Affibody molecules of different length were produced()by solid phase peptide synthesis (SPPS) and allowed to form covalently linked homodimers by S-S-bridges. The N-terminally truncated Affibody molecules Z(Aβ3)(12-58), Z(Aβ3)(15-58) and Z(Aβ3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(Aβ3)(1-58). Circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis showed that the shortest Affibody molecule - Z(Aβ3)(18-58) - exhibited complete loss of binding to the Aβ(1-40)-peptide, while the Z(Aβ3)(12-58) and Z(Aβ3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the Aβ(1-40)-peptide compared to the full-length Affibody molecule. Nuclear magnetic resonance (NMR) spectroscopy showed that the structure of Aβ(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the Aβ(1-40)-peptide in complex with the full-length Z(Aβ3) Affibody molecule. This indicates that the N-terminally truncated Affibody molecules Z(Aβ3)(12-58) and Z(Aβ3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric Aβ(1-40).PMID: 20886513 [PubMed - as supplied by publisher]
Related citations
44.
PLoS One. 2010 Sep 23;5(9):e12853.
Selective disruption of the cerebral neocortex in Alzheimer's disease.
Desikan RS, Sabuncu MR, Schmansky NJ, Reuter M, Cabral HJ, Hess CP, Weiner MW, Biffi A, Anderson CD, Rosand J, Salat DH, Kemper TL, Dale AM, Sperling RA, Fischl B; Alzheimer's Disease Neuroimaging Initiative.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America. rahul@nmr.mgh.harvard.edu
Abstract
BACKGROUND: Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.METHODOLOGY/PRINCIPAL FINDINGS: In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.
CONCLUSIONS/SIGNIFICANCE: Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.
PMID: 20886094 [PubMed - in process]PMCID: PMC2944799Free PMC Article
Related citations
45.
PLoS One. 2010 Sep 23;5(9):e12974.
Phospho-eIF2α level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice.
Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York, United States of America.
Abstract
β-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) generation and thus represents a prime therapeutic target in treating Alzheimer's disease (AD). Notably, increasing evidence indicates that BACE1 levels become elevated in AD brains as disease progresses; however, it remains unclear how the BACE1 upregulation may affect efficacies of therapeutic interventions including BACE1-inhibiting approaches. Here, we crossed heterozygous BACE1 knockout mice with AD transgenic mice (5XFAD model) and compared the abilities of partial BACE1 reduction to rescue AD-like phenotypes at earlier (6-month-old) and advanced (15-18-month-old) stages of disease, which expressed normal (∼100%) and elevated (∼200%) levels of BACE1, respectively. BACE1(+/-) deletion rescued memory deficits as tested by the spontaneous alternation Y-maze task in 5XFAD mice at the earlier stage and prevented their septohippocampal cholinergic deficits associated with significant neuronal loss. Importantly, BACE1(+/-) deletion was no longer able to rescue memory deficits or cholinergic neurodegeneration in 5XFAD mice at the advanced stage. Moreover, BACE1(+/-) deletion significantly reduced levels of Aβ42 and the β-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic β-cleavage products dramatically elevated with age and were not affected by BACE1(+/-) deletion in 15-18-month-old 5XFAD brains. Interestingly, although BACE1(+/-) deletion lowered BACE1 expression by ∼50% in 5XFAD mice irrespective of age in concordance with the reduction in gene copy number, BACE1 equivalent to wild-type controls remained in BACE1(+/-)·5XFAD mice at the advanced age. In accord, phosphorylation of the translation initiation factor eIF2α, an important mediator of BACE1 elevation, was dramatically increased (∼9-fold) in 15-18-month-old 5XFAD mice and remained highly upregulated (∼6-fold) in age-matched BACE1(+/-)·5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.PMID: 20886088 [PubMed - in process]PMCID: PMC2944882Free PMC Article
Related citations 46.
Magn Reson Med Sci. 2010;9(3):95-9.
Amyloid imaging using high-field magnetic resonance.
Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan.
Abstract
The formation of senile plaques followed by deposition of amyloid β peptides (Aβ) are the earliest pathological changes of Alzheimer's disease (AD); thus, detection of the plaques remains the most important early diagnostic indicator of AD. Amyloid imaging is a noninvasive technique for visualizing senile plaques in the brains of patients with Alzheimer's using positron emission tomography (PET) or magnetic resonance (MR) imaging. Several types of probes have been developed for PET, but few ligands have been developed specifically for MR imaging detection of amyloid plaques. This review presents recent advances in amyloid imaging using MR imaging and includes our studies.PMID: 20885081 [PubMed - in process]Free Article
Related citations
47.
Neuroscience. 2010 Sep 25. [Epub ahead of print]
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.PMID: 20884337 [PubMed - as supplied by publisher]
Related citations
48.
Eur J Pharmacol. 2010 Sep 29. [Epub ahead of print]
Involvement of notch signaling pathway in amyloid precursor protein induced glial differentiation.
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
Abstract
The amyloid precursor protein (APP) has been mainly studied in its role in the production of amyloid β peptides (Aβ), because Aβ deposition is a hallmark of Alzheimer's disease. Although several studies suggest APP has physiological functions, it is still controversial. We previously reported that APP increased glial differentiation of neural progenitor cells (NPCs). In the current study, NPCs transplanted into APP23 transgenic mice primarily differentiated into glial cells. In vitro treatment with secreted APP (sAPP) dose-dependently increased glial fibrillary acidic protein (GFAP) immuno-positive cells in NPCs and over expression of APP caused most NPCs to differentiate into GFAP immuno-positive cells. Treatment with sAPP also dose-dependently increased expression levels of GFAP in NT-2/D1 cells along with the generation of Notch intracellular domain (NICD) and expression of Hairy and enhancer of split 1 (Hes1). Treatment with γ-secretase inhibitor suppressed the generation of NICD and reduced Hes1 and GFAP expressions. Treatment with the N-terminal domain of APP (APP 1-205) was enough to induce up regulation of GFAP and Hes1 expressions, and application of 22 C11 antibodies recognizing N-terminal APP suppressed these changes by sAPP. These results indicate APP induces glial differentiation of NPCs through Notch signaling.PMID: 20883690 [PubMed - as supplied by publisher]
Related citations 49.
Protein Sci. 2010 Sep 29. [Epub ahead of print]
Structurally distinct toxicity inhibitors bind at common loci on β-amyloid fibril.
Department of Chemical & Biochemical Engineering, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore MD 21250.
Abstract
The accumulation of aggregated β-Amyloid (Aβ) in the brain is a hallmark of Alzheimer's Disease (AD) and is thought to play a role in the neurotoxicity associated with the disease. The mechanism by which Aβ aggregates induce toxicity is uncertain. Nonetheless, several small molecules have been found to interact with Aβ fibrils and to prevent their toxicity. In this paper we studied the binding of these known toxicity inhibitors to Aβ fibrils, as a means to explore surfaces or loci on Aβ aggregates that may be significant in the mechanism of action of these inhibitors. We believe knowledge of these binding loci will provide insight into surfaces on the Aβ fibrils important in Aβ biological activity. The program DOCK was used to computationally dock the inhibitors to an Aβ fibril. The inhibitors docked at two shared binding loci, near Lys28 and at the C-termini near Asn27 and Val39. The docking predictions were experimentally verified using lysine specific chemical modifications and Aβ fibrils mutated at Asn27. We found that both Congo red and Myricetin, despite being structurally different, bound at the same two sites. Additionally, our data suggests that three additional Aβ toxicity inhibitors may also bind in one of the sites. Identification of these common binding loci provides targets on the Aβ fibril surface that can be tested in the future for their role in Aβ biological activity.PMID: 20882638 [PubMed - as supplied by publisher]
Related citations 50.
Neurosci Bull. 2010 Oct;26(5):417-27.
Regulation of β cleavage of amyloid precursor protein.
Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes of Biological Sciences, State Key Laboratory of Neuroscience, Shanghai 200031, China.
Abstract
Alzheimer's disease ranks the first cause for senile dementia. The amyloid cascade is proposed to contribute to the pathogenesis of this disease. In this cascade, amyloid β peptide (Aβ) is produced through a sequential cleavage of amyloid precursor protein (APP) by β and γ secretases, while its cleavage by α secretase precludes Aβ production and generates neurotrophic sAPPα. Thus, enhancing α secretase activity or suppressing β and γ cleavage may reduce Aβ formation and ameliorate the pathological process of the disease. Several regulatory mechanisms of APP cleavage have been established. The present review mainly summarizes the signaling pathways pertinent to the regulation of APP β cleavage.PMID: 20882069 [PubMed - in process]
Related citations51.
J Neurosci. 2010 Sep 29;30(39):13110-5.
Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex.
Department of Neurology and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract
SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer's disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid-β peptide (Aβ) and the Aβ precursor protein (APP), to test the hypothesis that Sorcs1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1cβ-myc in cultured cells caused a reduction (p = 0.002) in Aβ generation. Conversely, endogenous murine Aβ(40) and Aβ(42) levels were increased (Aβ(40), p = 0.044; Aβ(42), p = 0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1cβ-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p = 0.009) and total SorL1 protein levels were decreased by 29% (p = 0.003) in the brains of female Sorcs1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Aβ disturbance underlying AD and the insulin/glucose disturbance underlying DM.PMID: 20881129 [PubMed - in process]
Related citations
52.
J Neurosci. 2010 Sep 29;30(39):13089-94.
Transgenic mice with chronic NGF deprivation and Alzheimer's disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities.
Laboratory of Molecular Mechanisms of Synaptic Plasticity, European Brain Research Institute, 00143 Rome, Italy.
Abstract
The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated β-amyloid peptide (Aβ) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to Aβ accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including Aβ accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short- and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation).PMID: 20881126 [PubMed - in process]
Related citations 53.
Phytother Res. 2010 Oct;24(10):1538-42.
Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells.
School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Abstract
Amyloid β peptide (Aβ) induced toxicity is a well-established pathway of neuronal cell death which might play a role in Alzheimer's disease. In this regard, the toxic effect of Aβ on a cultured Aβ-sensitive neuronal cell line was used as a primary screening tool for potential anti-Alzheimer's therapeutic agents. The effects of nine pure compounds (vitamin E, α-asarone, salidroside, baicolin, magnolol, gastrodin, bilobalide, honokiol and β-asarone) from selected Chinese herbs on neuronal cell death induced by Aβ in NGF-differentiated PC12 cells were examined. Only two of the studied compounds, honokiol and magnolol, significantly decreased Aβ-induced cell death. Further experiments indicated that their neuroprotective effects are possibly mediated through reduced ROS production as well as suppression of intracellular calcium elevation and inhibition of caspase-3 activity. The results provide for the first time a scientific rationale for the clinical use of honokiol and magnolol in the treatment of Alzheimer's disease.PMID: 20878707 [PubMed - in process]
Related citations 54.
J Biol Chem. 2010 Sep 28. [Epub ahead of print]
Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated IDE secretion.
Tamboli IY, Barth E, Christian L, Siepmann M, Singh S, Tolksdorf K, Heneka MT, Luetjohann D, Wunderlich P, Walter J.
University Hospital Bonn, Germany;
Abstract
Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer's disease (AD). Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid β-peptide (Aβ) from the β-amyloid precursor protein (APP). Here, we show that statins potently stimulate the degradation of extracellular Aβ by microglia. The statin-dependent clearance of extracellular Aβ is mainly exerted by insulin degrading enzyme (IDE) which is secreted in a non-conventional pathway in association with exosomes. Stimulated IDE secretion and Aβ degradation was also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and upregulation of exosome secretion by fusion of multivesicular bodies (MVBs) with the plasma membrane. These data demonstrate a novel pathway for the non-conventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of Aβ.PMID: 20876579 [PubMed - as supplied by publisher]Free Article
Related citations
55.
Neuroscience. 2010 Sep 27. [Epub ahead of print]
Cloning, sequencing and expression in the dog of the main amyloid precursor protein isoforms and some of the enzymes related with their processing.
Montecanal Laboratory, Araclon Biotech, Zaragoza, Spain.
Abstract
Alzheimer's disease (AD) is characterized by neuronal loss and the presence of both neurofibrillary tangles and senile plaques in the brain. These plaques arise from the deposition of beta-amyloid (Aβ) peptides (38-43 amino acids), which are generated from enzymatic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. In the present work, we cloned the principal APP isoforms as well as some enzymes that have been implicated in their amyloidogenic and non-amyloidogenic processing in dogs. Additionally, the main proteases implicated in the degradation of Aβ were also studied. We also investigated the level of expression of these APP isoforms and enzymes in different brain regions and in peripheral tissues. Our data demonstrate that these canine proteins are highly homologous to their human counterparts. In addition, the expression pattern of these proteins in dogs is consistent with previous data reported in human beings. Thus, dogs may be a natural model to study the biology of AD and could also serve as an animal model for Aβ-targeted drugs against this devastating disease.PMID: 20875843 [PubMed - as supplied by publisher]
Related citations 56.
Brain Res. 2010 Sep 25. [Epub ahead of print]
Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease.
Thorsell A, Bjerke M, Gobom J, Brunhage E, Vanmechelen E, Andreasen N, Hansson O, Minthon L, Zetterberg H, Blennow K.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
Abstract
Synaptic pathology occurs early in Alzheimer's disease (AD) development, and cerebrospinal fluid biomarkers for synaptic damage may be altered early in the disease process. In the present study we examined cerebrospinal fluid levels of the postsynaptic protein neurogranin in patients with mild cognitive impairment (MCI) or AD and controls. The low neurogranin level in cerebrospinal fluid required enrichment by immunoprecipitation prior to mass spectrometric identification and semi-quantitative immunoblot analysis. Relative quantification revealed a significant increase of neurogranin in the AD group compared with controls, while the MCI group was not statistically different from either controls or the AD group. The concentration of the AD biomarkers T-tau, P-tau(181) and Aβ(42) were significantly changed in the control and MCI groups compared with the AD group, but no significant differences were found between the MCI group and controls for the three biomarkers. Nevertheless, a trend towards increasing levels of neurogranin, T-tau and P-tau(181) was found in cerebrospinal fluid from MCI patients compared with controls. The elevated neurogranin levels in the MCI and AD groups might reflect synaptic degeneration. These results together suggest that cerebrospinal fluid neurogranin might be valuable together with the established AD biomarkers in the early diagnosis of AD and warrants further studies to determine the diagnostic value of neurogranin.PMID: 20875798 [PubMed - as supplied by publisher]
Related citations 57.
J Am Chem Soc. 2010 Sep 28. [Epub ahead of print]
Combination of Kinetically Selected Inhibitors in Trans Leads to Highly Effective Inhibition of Amyloid Formation.
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, and Department of Medicine, New York University Medical Center, 550 First Avenue, New York, New York 10016.
Abstract
Amyloid formation plays a role in over 25 human disorders. A range of strategies have been applied to the problem of developing inhibitors of amyloid formation, but unfortunately, many inhibitors are effective only in molar excess and typically either lengthen the time to the onset of amyloid formation, (the lag time), while having modest effects on the total amount of amyloid fibrils produced, or decrease the amount of amyloid without significantly reducing the lag time. We demonstrate a general strategy whereby two moderate inhibitors of amyloid formation can be rationally selected via kinetic assays and combined in trans to yield a highly effective inhibitor which dramatically delays the time to the appearance of amyloid and drastically reduces the total amount of amyloid formed. A key feature is that the selection of the components of the mixture is based on their effect on the time course of amyloid formation rather than on just the amount of amyloid produced. The approach is validated using inhibitors of amyloid formation by islet amyloid polypeptide, the causative agent of amyloid formation in type 2 diabetes and the Alzheimer's disease Aβ peptide.PMID: 20873820 [PubMed - as supplied by publisher]
Related citations58.
Zhong Yao Cai. 2010 May;33(5):763-7.
[The protective effect of puerarin on Abeta(25-35)-induced PC12 cell injury]
[Article in Chinese]
Department of Anatomy, Hainan Medical College, Haikou 571101, China. hyzhang_xjtu@yahoo.cn
Abstract
OBJECTIVE: To study The protective effect of puerarin on Abeta(25-35)-induced PC12 cell injury.METHODS: PC12 cells were treated with puerarin for 0.5 h, then incubated with Abeta(25-35) (50 micromol/L) for 24 h to investigate the production of reactive oxygen species (ROS), mitochondrial membrane potential levels and Caspase-3 activation; The expressions of Bax, bcl-2 were measured by Western Blotting.
RESULTS: Preincubation of the cell with puerarin could inhibit the ROS and increase mitochondrial membrane potential levels. Puerarin was also found to increase the Bcl-2/Bax ratio and reduce Caspase-3 activation.
CONCLUSION: Puerarin may act as an intracellular ROS scavenger, and its antioxidant properties may protect against Abeta(25-35)-induced cell injury.
PMID: 20873562 [PubMed - in process]
Related citations59.
Biopolymers. 2010 Sep 24. [Epub ahead of print]
CD measurements of β-amyloid (1-40) and (1-42) in the condensed phase.
Japan Science and Technology Agency, ERATO-SORST Kuroda Chiromorphology Team, 4-7-6 Komaba, Meguro-ku, Tokyo, 153-0041, Japan.
Abstract
Circular Dichroism (CD) spectroscopy of proteins/peptides in thin films can provide valuable information on the structures in the aggregated states, however, it is difficult to estimate the secondary structure content quantitatively due to artifact signals arising from macroscopic anisotropies which is unique to the solid phase. Using a Universal Chiroptical Spectrophotometer (UCS-1) together with the measurement and analytical procedures we have developed, we could obtain artifact-free CD spectra of cast and Langmuir-Blodgett (L-B) films of synthetic peptides, Aβ (1-40) and (1-42) which are related to Alzheimer's disease. The work gave insights into the mechanisms for structural transformation and amyloid-like aggregation. © 2010 Wiley Periodicals, Inc. Biopolymers, 2010.PMID: 20872872 [PubMed - as supplied by publisher]
Related citations 60.
Int J Alzheimers Dis. 2010 Aug 12;2010. pii: 723782.
Neuron loss in transgenic mouse models of Alzheimer's disease.
Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Goettingen, von-Siebold-Str. 5, 37075 Goettingen, Germany.
Abstract
Since their initial generation in the mid 1990s, transgenic mouse models of Alzheimers's disease (AD) have been proven to be valuable model systems which are indispensable for modern AD research. Whereas most of these models are characterized by extensive amyloid plaque pathology, inflammatory changes and often behavioral deficits, modeling of neuron loss was much less successful. The present paper discusses the current achievements of modeling neuron loss in transgenic mouse models based on APP/Aβ and Tau overexpression and provides an overview of currently available AD mouse models showing these pathological alterations.PMID: 20871861 [PubMed - in process]PMCID: PMC2943100Free PMC Article
Related citations 
Wow! Finally I got a web site from where I be
ReplyDeletecapable of genuinely obtain helpful data regarding my
study and knowledge.
my homepage: Belinda Broido