Journal of Alzheimer's Disease - Volume 21, issue 2

Authors: Avila, Jesus | Hernandez, Felix | Wandosell, Francisco | Lucas, Jose J. | Esteban, Jose A. | Ledesma, M. Dolores | Bullido, Maria J.

Article Type: Research Article

Abstract: One important aspect of studies carried out at the Center for Molecular Biology “Severo Ochoa” is focused on basic aspects of Alzheimer's disease, mainly the search for suitable therapeutic targets for this disorder. Several groups at the Center are involved in these studies, and, in this spotlight, the work they are carrying out will be described.

DOI: 10.3233/JAD-2010-100912

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 325-335, 2010

Authors: Martínez-Martín, Pablo | Ávila, Jesús | AD Research Unit Investigators

Article Type: Research Article

Abstract: As the impact of Alzheimer's disease (AD) on society expands, the reaction aimed at neutralizing its effects also increases. In Spain, an initiative arisen from the highest institution of the State has launched a crusade for fighting the disease from a multidisciplinary stance. In 2002, the “Alzheimer Project” of the Reina Sofia Foundation was announced and in 2007, the Alzheimer Center Reina Sofia Foundation was inaugurated. This resource includes a long-term inpatient care facility, a day-care center, premises for education and training, and a research unit. This way, patients and investigators share the space in a clear expression of “translational …research”. The Research Unit is managed by the CIEN Foundation, Carlos III Institute of Health, an entity depending on the Ministry of Science and Innovation, and financed in part by the Reina Sofia Foundation. It includes clinical and social research, laboratory, neuroimaging (MRI 3T), and biobank facilities. The connection of the Unit with other research centers and laboratories (both in Spain and outside), universities, and associations of AD patients' relatives is tight and facilitates a dynamic collaboration. The involvement of all social strata in the Alzheimer Project makes evident the unitary effort that Spain is carrying out in the fight against neurodegenerative diseases and, particularly, AD. Show more

DOI: 10.3233/JAD-2010-101149

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 337-348, 2010

Authors: Burrell, James R. | Hodges, John R.

Article Type: Review Article

Abstract: Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also …a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries. Show more

Keywords: Behavioral variant FTD, frontotemporal dementia, FTD-ALS, progressive non-fluent aphasia, semantic dementia, tau, TDP-43

DOI: 10.3233/JAD-2010-091513

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 349-360, 2010

Authors: Bar-Am, Orit | Amit, Tamar | Weinreb, Orly | Youdim, Moussa B.H. | Mandel, Silvia

Article Type: Review Article

Abstract: The anti-Parkinsonian, irreversible, selective monoamine oxidase (MAO)-B inhibitors, selegiline (deprenyl, (R)-N-methyl-N-(1-phenylpropan-2-yl) prop-2-yn-1-amine) and rasagiline (Azilect, N-propargyl-1(R)-aminoindan), have been proven to possess neuroprotective/neurorestorative activities in cell cultures and animal models of neurodegenerative diseases. Structure-activity studies provide evidence that neuroprotection is associated with some intrinsic pharmacological action of the propargylamine moiety in these drugs. This indication and recent therapeutic approaches, entailing new drug candidates possessing diverse pharmacological properties and acting on multiple targets, have stimulated the development of two multifunctional chimeric propargylamine-derivatives: 1) ladostigil (TV3326, [(N-propargyl-(3R) 1-(R)-aminoindan-5yl)-ethyl methyl carbamate)], which combines the pharmacophore of rasagiline, with the carbamate moiety of the cholinesterase …inhibitor rivastigmine, as a potential treatment for Alzheimer's disease and Lewy body disease; and 2) M30 5-[(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], where the propargylamine moiety of rasagiline was embedded onto the backbone of the neuroprotective and brain permeable iron chelator 8-hydroxyquinoline-derivative, VK28 as a potential treatment for various neurodegenerative disorders. Both multifunctional propargylamine-derivatives were found to possess neuroprotective and anti-apoptotic properties. An additional and new neuroprotective effect, shared by the propargylamine-derivative compounds, is related to their ability to regulate the processing of amyloid-β protein precursor (AβPP) by the non-amyloidogenic α-secretase pathway. This effect was shown to involve activation of p42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathway. This review will summarize and discuss current research, focused on the effect of propargylamine-related derivatives on the proteolytic processing of AβPP and signal transduction mechanisms. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, amyloid-β protein precursor (AβPP), mitogen-activated protein kinase (MAPK), multifunctional drugs, protein kinase C (PKC), propargylamine-derivatives, sAβPP

DOI: 10.3233/JAD-2010-100150

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 361-371, 2010

Authors: Marques, Sueli C.F. | Oliveira, Catarina R. | Outeiro, Tiago F. | Pereira, Claudia M.F.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a complex disorder of the central nervous system that affects an increasing number of people worldwide due to the overall aging of the human population. In addition to genetics, which accounts for a small fraction of all cases, the etiology is multifactorial with other currently unknown triggers. It is crucial to unravel the physiological mechanisms that, being disrupted, could lead to neurodegeneration, as this knowledge could ultimately lead to the identification of novel neuroprotective strategies that could be used as therapeutics. Although mitochondrial dysfunction and the resultant oxidative stress are believed to play a major role …in the pathogenesis of both early- and late-onset AD, it is conceivable that the altered physiological state of the cells leading to sporadic AD could involve additional mechanisms. Much evidence suggests that epigenetic modification of gene expression can accumulate with age leading to an altered response to stress and to an enhanced susceptibility to diseases. Since aging has a major impact in different late-onset, complex diseases and, in particular, in the late-onset forms of AD, epigenetic alterations might play an important role in the pathophysiology of this disorder. Studies exploring this idea are underway and suggest that both methylation abnormalities in AD-related genes due to disruption of mechanisms that regulate the availability of methyl groups (SAM/HCY cycle) and changes of global histone acetylation levels might play a role in neurodegeneration. Thus, it is essential to undertake novel global approaches, which may lead to the development of new avenues for therapeutic intervention. Show more

Keywords: DNA methylation, epigenetics, histone modifications, neurodegeneration

DOI: 10.3233/JAD-2010-100303

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 373-383, 2010

Authors: Lescai, Francesco | Pirazzini, Chiara | D'Agostino, Giuseppe | Santoro, Aurelia | Ghidoni, Roberta | Benussi, Luisa | Galimberti, Daniela | Federica, Esposito | Marchegiani, Francesca | Cardelli, Maurizio | Olivieri, Fabiola | Nacmias, Benedetta | Sorbi, Sandro | Bagnoli, Silvia | Tagliavini, Fabrizio | Albani, Diego | Boneschi, Filippo Martinelli | Binetti, Giuliano | Forloni, Gianluigi | Quadri, Pierluigi | Scarpini, Elio | Franceschi, Claudio

Article Type: Short Communication

Abstract: A recent genome-wide study on late-onset Alzheimer's disease identified a SNP (rs5984894) on Xq21.3 in the PCDH11X gene strongly associated with LOAD individuals of European descent from the United States. We genotyped the same polymorphism in 1222 cases and 938 controls from central-northern Italy and could not confirm the association on the Italian population: multivariate logistic regression adjusted for gender and APOE ε4 allele resulted in a global p value of 0.56.

Keywords: Alzheimer's disease, APOE, genetics, replication

DOI: 10.3233/JAD-2010-091516

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 385-388, 2010

Authors: Zhang, Shouting | Hedskog, Louise | Petersen, Camilla A. Hansson | Winblad, Bengt | Ankarcrona, Maria

Article Type: Research Article

Abstract: Dimebon, a drug currently being evaluated in multiple Phase III Alzheimer's disease trials, has previously been shown to have effects on isolated mitochondria at μM concentrations. Here the effects of nM concentrations of Dimebon on mitochondrial function were investigated both in primary mouse cortical neurons and human neuroblastoma cells (SH-SY5Y). Under non-stress conditions nM concentrations of Dimebon increased succinate dehydrogenase activity (MTT-assay), mitochondrial membrane potential (ΔΨm), and cellular ATP levels. Dimebon treatment had no effect on mitochondria DNA content, implying that mitochondrial biogenesis was not induced. Under stress conditions, mitochondria in Dimebon-treated neurons showed increased resistance to elevated intracellular calcium …concentrations, thus, maintaining their ΔΨm throughout the experiment, in contrast to control neurons, which rapidly lost their ΔΨm. Moreover, we show that serum-starved differentiated SH-SY5Y cells treated with Dimebon had an increased survival rate as compared to untreated cells. In conclusion, these data demonstrate that Dimebon enhances mitochondrial function both in the absence and presence of stress and Dimebon-treated cells are partially protected to maintain cell viability. Show more

Keywords: Alzheimer's disease, Dimebon (latrepirdine), mitochondria, neuronal cells

DOI: 10.3233/JAD-2010-100174

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 389-402, 2010

Authors: Sharman, Matthew J. | Morici, Michael | Hone, Eugene | Berger, Tamar | Taddei, Kevin | Martins, Ian J. | Lim, Wei Ling F. | Singh, Sajla | Wenk, Markus R. | Ghiso, Jorge | Buxbaum, Joseph D. | Gandy, Sam | Martins, Ralph N.

Article Type: Research Article

Abstract: The ε4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-β (Aβ) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE-/- mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic Aβ42 in APOE ε2, ε3, and ε4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does …influence the rate at which the mice are able to clear Aβ42 from their bloodstream. Both APOE ε4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Aβ42 over time compared to APOE ε2/APOE knock-out rE2 and APOE ε3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Aβ42 is significantly altered by APOE genotype. Given that APOE ε4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Aβ which may impact on clearance from the brain. Show more

Keywords: Alzheimer's disease, amyloid-β, APOE genotype, peripheral sink hypothesis

DOI: 10.3233/JAD-2010-100141

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 403-409, 2010

Authors: Cantero, Jose L. | Hita-Yañez, Eva | Moreno-Lopez, Bernardo | Portillo, Federico | Rubio, Alicia | Avila, Jesus

Article Type: Research Article

Abstract: Evidence has shown that the lack of tau produces subtle changes in neuronal structure and modest impairment in complex behaviors, suggesting compensatory mechanisms carried out by other neuronal microtubule-associated proteins. Here we show major abnormalities in sleep-wake cycle of tau-deficient animals including increased wakefulness duration and decreased non-rapid eye movement (NREM) sleep time, a higher number of state transitions between NREM and wake, and shortened sleep bouts. Altered sleep structure in tau-/- mice was accompanied by a significant decline in delta power together with an enhanced spectral density of sleep spindles during NREM sleep. No significant differences were observed …in rapid eye movement (REM) sleep between the two mouse strains. Taken together, these results suggest that tau indirectly participates in the regulation of the sleep-wake cycle modulating not only the control and maintenance of global brain states but also the cerebral oscillatory patterns underlying sleep-wake states. Show more

Keywords: Animal models, local field potential, microtubule-associated proteins, neuronal cytoskeleton, sleep-wake regulation, state-dependent brain oscillations, tau

DOI: 10.3233/JAD-2010-100285

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 411-421, 2010

Authors: Brouwers, Nathalie | Bettens, Karolien | Gijselinck, Ilse | Engelborghs, Sebastiaan | Pickut, Barbara A. | Van Miegroet, Helen | Montoya, Ana Gil | Mattheijssens, Maria | Peeters, Karin | De Deyn, Peter P. | Cruts, Marc | Sleegers, Kristel | Van Broeckhoven, Christine

Article Type: Research Article

Abstract: The nuclear transactive response (TAR) DNA binding protein-43, TDP-43, is a major constituent of the ubiquitinated neuronal inclusions in patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Missense mutations in TDP-43 have been associated with familial and sporadic ALS. Since TDP-43 immunoreactivity was also frequently observed in Alzheimer's disease (AD) brains and elevated TDP-43 plasma levels were detected in a subset of AD patients, we sequenced the TDP-43 gene, TARDBP, in a well-documented group of AD patients (n=485). We observed one mutation in exon 3 (c.269C>T) predicting a p.Ala90Val substitution in two patients. One extra p.Ala90Val carrier …was observed by sequencing exon 3 of an additional set of 254 AD patients. The mutation was absent from 604 control individuals. Allele and haplotype analysis using microsatellite markers suggested that the three patients might share a common founder. However, co-segregation of p.Ala90Val with AD could not be realized leaving its pathogenic unclear at this moment. Also, sequencing in 190 additional AD patients of TARDBP exon 6 in which pathogenic mutations have been reported in FTLD and ALS was negative. Further, genetic association analyses using five single nucleotide polymorphisms did not detect significant differences between AD patients and control individuals. In conclusion, the genetic contribution of TARDBP to AD was restricted to the rare mutation p.Ala90Val (3/739, 0.4%) of unclear pathogenic nature that affects the nuclear localization signal in TDP-43. Show more

Keywords: Alzheimer's disease, association analysis, genetics, mutation analysis, TARDBP

DOI: 10.3233/JAD-2010-100198

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 423-430, 2010

Authors: Magini, Alessandro | Urbanelli, Lorena | Ciccarone, Virginia | Tancini, Brunella | Polidoro, Mario | Timperio, Anna Maria | Zolla, Lello | Tedde, Andrea | Sorbi, Sandro | Emiliani, Carla

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), a major goal is to improve early detection, as the diagnosis cannot be made until patients exhibit a noticeable decline in cognition and the brain is irreversibly damaged. With this aim in mind, we performed proteome analysis of familial AD fibroblasts from both demented and pre-symptomatic subjects, using a 2D-PAGE based approach and then identifying proteins by mass spectrometry. We compared primary fibroblast cultures from skin biopsy of presenilin 1 (PS1) mutated patients, pre-symptomatic subjects carrying mutations in the PS1 gene but healthy at the time of skin biopsy, and age-matched individuals as control. 15 differentially …expressed proteins were identified in PS1 mutated fibroblasts, related to cell adhesion and cytoskeleton, energy and glucose metabolism, stress response and ubiquitin-proteasome system, and signal transduction. Interestingly, many of these proteins have been previously associated with AD and neurodegeneration. Overall results indicated that a unique protein profile can be identified by peripheral cell analysis of PS1 mutated individuals, and showed that fibroblasts are a useful cell model for pathological investigations as well as identification of potential biomarkers for AD diagnosis at early stages. Show more

Keywords: Alzheimer's disease, early markers, proteome analysis, skin fibroblasts

DOI: 10.3233/JAD-2010-091522

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 431-444, 2010

Authors: Amadoro, Giuseppina | Corsetti, Veronica | Stringaro, Annarita | Colone, Marisa | D'Aguanno, Simona | Meli, Giovanni | Ciotti, MariaTeresa | Sancesario, Giuseppe | Cattaneo, Antonino | Bussani, Rossana | Mercanti, Delio | Calissano, Pietro

Article Type: Research Article

Abstract: Synapses are ultrastructural sites for memory storage in brain, and synaptic damage is the best pathologic correlate of cognitive decline in Alzheimer's disease (AD). Post-translational hyperphosphorylation, enzyme-mediated truncation, conformational modifications, and aggregation of tau protein into neurofibrillary tangles (NFTs) are hallmarks for a heterogeneous group of neurodegenerative disorders, so-called tauopathies. AD is a secondary tauopathy since it is pathologically distinguished by the presence of amyloid-β (Aβ)-containing senile plaques and the presence of tau-positive NFTs in the neocortex and hippocampus. Here, we report that a 20–22 kDa NH2 -truncated tau fragment is largely enriched in human mitochondria from cryopreserved synaptosomes of …AD brains and that its amount in terminal fields correlates with the pathological synaptic changes and with the organelle functional impairment. This NH2 -truncated tau form is also found in other human, not AD-tauopathies, while its presence in AD patients is linked to Aβ multimeric species and likely to pathology severity. Finally native, patient-derived, Aβ oligomers-enriched extracts likely impair the mitochondrial function by the in vitro production of 20–22 kDa NH2 -tau fragments in mature human SY5Y and in rat hippocampal neurons. Thus our findings suggest that the mitochondrial NH2 -derived tau peptide distribution may exacerbate the synapse degeneration occurring in tauopathies, including AD, and sustain the in vivo NH-2 tau cleavage inhibitors as an alternative drug discovery strategies for AD therapy. Show more

Keywords: Alzheimer's disease, amyloid, mitochondria, neurodegeneration, synapse(s), tau

DOI: 10.3233/JAD-2010-100120

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 445-470, 2010

Authors: Sundelöf, Johan | Sundström, Johan | Hansson, Oskar | Eriksdotter-Jönhagen, Maria | Giedraitis, Vilmantas | Larsson, Anders | Degerman-Gunnarsson, Malin | Ingelsson, Martin | Minthon, Lennart | Blennow, Kaj | Kilander, Lena | Basun, Hans | Lannfelt, Lars

Article Type: Research Article

Abstract: Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-β (Aβ) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Aβ42 , and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Aβ42 , and tau levels in CSF in AD, MCI, and controls. As a secondary aim, the relationships between cystatin C, Aβ42 , and tau levels across …disease groups were investigated. Cystatin C, Aβ42 , total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Aβ and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Mean cystatin C levels were similar in cases of AD (5.6 μmol/L ± 1.7), MCI (5.4 μmol/L ± 1.48), and controls (5.6 μmol/L ± 1.6). However, CSF cystatin C levels were strongly and positively correlated with total tau and phosphorylated tau levels (r=0.61–0.81, p< 0.0001) and Aβ42 (r=0.35–0.65, p< 0.001) independent of age, gender, and APOE genotype. Mean CSF cystatin C levels did not differ between patients with AD and MCI and healthy controls. Interestingly, cystatin C levels were positively correlated with both tau and Aβ42 levels in CSF independent of age, gender, and APOE genotype. Show more

Keywords: Alzheimer's disease, biomarkers, case control study, cystatin C, epidemiology, risk factor

DOI: 10.3233/JAD-2010-091594

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 471-478, 2010

Authors: Stefanova, Natalia A. | Fursova, Anzhela Zh. | Kolosova, Nataliya G.

Article Type: Research Article

Abstract: Mitochondrial dysfunction is involved in aging and in neurodegenerative diseases and, therefore, pharmacological agents that alleviate mitochondrial dysfunction are expected to have neuroprotective effects. Promising in this respect is mitochondrial-targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1). We investigated the effects of SkQ1 (250 nmol SkQ1/kg × day with food) on behavior in the elevated plus-maze (EPM) and open field (OF) and on spatial memory in a Morris water maze (MWM) in middle-aged (12 mo) Wistar and senescence-accelerated OXYS rats. Given that changes in the behavior of OXYS rats may be associated with visual impairment, the condition of the retina and the lens was …evaluated by ophthalmoscopy. 14-month-old as well as 3-month-old OXYS rats had considerably reduced activities in OF, increased anxiety in EPM, and manifested impaired learning abilities in the MWM in comparison with Wistar rats. SkQ1-treated rats of both strains displayed significantly higher locomotor and exploratory activity in the OF and less anxiety in the EPM compared to age-matched controls. SkQ1 significantly improved visual ability of the rats reducing the severity of the developed signs of retinopathy and cataract but had no impact on OXYS rat's spatial memory in the MWM. SkQ1-treated Wistar rats exhibited slower learning in the MWM task comparison to the control group. Thus, SkQ1 had beneficial effects on locomotor and exploratory functions of the rat brain. Nevertheless, SkQ1 did not alter learning performance in the MWM in OXYS rats and slightly reduced it in the Wistar strain, which may be associated with differences in redox homeostasis. Show more

Keywords: Behavior, brain aging, mitochondrial-targeted antioxidant SkQ1, senescence-accelerated OXYS rats

DOI: 10.3233/JAD-2010-091675

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 479-491, 2010

Authors: Huang, Wen | Niu, Hai | Xue, Xinsheng | Li, Junxiang | Li, Chenwei

Article Type: Research Article

Abstract: Acrolein is a highly electrophilic α, β-unsaturated aldehyde to which humans are exposed in many situations and has been implicated in neurodegenerative diseases such as Alzheimer's disease. A galloyl dimer prorobinetinidin from Acacia mearnsii De Wild , robinetinidol-(4β→8)-epigallocatechin 3-O-gallate (REO), has antioxidant properties and could protect brain against acrolein-induced oxidative damage. In this study, the molecular basis of acrolein-induced cytotoxicity in human neuroblastoma SH-SY5Y cells and the modulating effects of REO were examined. Our results indicate that REO protects SH-SY5Y cells from acrolein-induced damage by the attenuation of reactive oxygen species, the remediation of NADPH oxidase activity, the enhancement of …the glutathione system, and the prevention of protein oxidation/nitration and lipid peroxidation. In order to determine the effects of REO on mitochondrial events, mitochondrial membrane potentials (Δ Ψm) and caspase cascades downstream of mitochondria were assessed. REO inhibited the collapse of Δ Ψ m, suggesting that REO reduces the mitochondrial dysfunction associated with acrolein treatment. REO also inhibited caspase-3 activation, which can be triggered by mitochondrial malfunctions. Furthermore, REO induced a significant reduction in the level of phospho-JNK, which is known as an apoptotic mediator in acrolein-induced neuronal cell death. Our results indicate that REO protects neurons from the deleterious effects of acrolein via the attenuation of oxidative stress, NADPH oxidase activity, GSH depletion, protein oxidation/nitration, lipid peroxidation, mitochondrial dysfunction, JNK activation, and caspase activity. These findings suggest that REO could be potentially useful as a protective agent for people exposed to acrolein. Show more

Keywords: Flavonoids, neurodegenerative diseases, oxidative stress, reactive oxygen species

DOI: 10.3233/JAD-2010-090886

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 493-506, 2010

Authors: Boyd, Tim D. | Bennett, Steven P. | Mori, Takashi | Governatori, Nicholas | Runfeldt, Melissa | Norden, Michelle | Padmanabhan, Jaya | Neame, Peter | Wefes, Inge | Sanchez-Ramos, Juan | Arendash, Gary W. | Potter, Huntington

Article Type: Research Article

Abstract: Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer's disease (AD). While it has been commonly assumed that RA patients' usage of non-steroidal anti-inflammatory drugs (NSAIDs) helped prevent onset and progression of AD, NSAID clinical trials have proven unsuccessful in AD patients. To determine whether intrinsic factors within RA pathogenesis itself may underlie RA's protective effect, we investigated the activity of colony-stimulating factors, upregulated in RA, on the pathology and behavior of transgenic AD mice. 5 μg bolus injections of macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factors (M-CSF, G-CSF, or GM-CSF) were administered unilaterally into the hippocampus …of aged cognitively-impaired AD mice and the resulting amyloid load reductions determined one week later, using the artificial cerebrospinal fluid-injected contralateral sides as controls. G-CSF and more significantly, GM-CSF reduced amyloidosis throughout the treated brain hemisphere one week following bolus administration to AD mice. 20 daily subcutaneous injections of 5μg of GM-CSF (the most amyloid-reducing CSF in the bolus experiment) were administered to balanced cohorts of AD mice after assessment in a battery of cognitive tests. Reductions in amyloid load and improvements in cognitive function were assessed. Subcutaneous GM-CSF administration significantly reduced brain amyloidosis and completely reversed the cognitive impairment, while increasing hippocampal synaptic area and microglial density. These findings, along with two decades of accrued safety data using Leukine, recombinant human GMCSF, in elderly leukopenic patients, suggest that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cognitive interference task, granulocyte-macrophage colony-stimulating factor, intrahippocampal, radial arm water maze, rheumatoid arthritis, subcutaneous, transgenic mice

DOI: 10.3233/JAD-2010-091471

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 507-518, 2010

Authors: van Beek, Arenda H.E.A. | Sijbesma, Jaap C. | Jansen, Rene W.M.M. | Rikkert, Marcel G.M. Olde | Claassen, Jurgen A.H.R.

Article Type: Research Article

Abstract: Cerebrovascular function and structure of the cortical cerebral microvessels are profoundly altered in patients with Alzheimer's disease (AD). The functional hemodynamic consequences of such changes, however, remain essentially unknown. Cholinesterase inhibitors (ChEIs) potentially affect brain perfusion through either augmentation or inhibition of cerebral vasodilatation. This study investigated the cerebrovascular regulation during postural changes in AD before and after treatment with the ChEI galantamine. In 21 AD patients and 20 controls, blood pressure (BP – Finapres), frontal cortical oxygenation (near-infrared-spectroscopy), and cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography) were measured following a hypotensive challenge induced by …postural change. In AD, measurements were repeated after 10 (SD 4) weeks of galantamine. Baseline cerebrovascular resistance was higher in AD (AD 2.83 (0.87) mmHg/cm/s, control 2.24 (1.3) mmHg/cm/s, p=0.010). 13 AD patients and 17 controls had a sufficiently large postural drop in BP (> 10 mmHg). AD patients had a larger postural decline in the frontal cortical concentration of total hemoglobin (Δ [tHb] AD=1.03 (0.70) μmol/l, control =0.30 (0.90) μmol/l, p=0.015). Moreover, the reduction in oxygenated hemoglobin was 57% larger in AD (p=0.085). Unexpectedly, the postural changes in BP were smaller in AD. Galantamine treatment affected neither orthostatic BP nor the decrease in [tHb]. In conclusion, even for moderate orthostatic hypotension during commonly occurring postural changes, cerebral cortical tissue perfusion declined more in AD, suggesting increased ischemic vulnerability of the brain. Galantamine neither improved nor impaired cerebrovascular regulation. Show more

Keywords: Alzheimer's disease, cerebral blood flow, cholinesterase inhibitors, near-infrared spectroscopy, transcranial Doppler ultrasonography

DOI: 10.3233/JAD-2010-100288

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 519-526, 2010

Authors: Parachikova, Anna | Vasilevko, Vitaly | Cribbs, David H. | LaFerla, Frank M. | Green, Kim N.

Article Type: Research Article

Abstract: Cognitive decline in Alzheimer's disease (AD) occurs as a result of the buildup of pathological proteins and downstream events including an elevated and altered inflammatory response. Inflammation has previously been linked to increased abnormal phosphorylation of tau protein. To determine if endogenous amyloid-β (Aβ)-induced neuroinflammation drives tau phosphorylation in vivo, we treated 8-month-old 3xTg-AD with minocycline, an anti-inflammatory agent, to assess how it influenced cognitive decline and development of pathology. 4 months of treatment restored cognition to non-transgenic performance. Inflammatory profiling revealed a marked decrease in GFAP, TNFα, and IL6 and an increase in the CXCL1 chemokines KC and MIP1a. …Minocycline also reduced levels of insoluble Aβ and soluble fibrils. Despite reducing levels of the tau kinase cdk5 coactivator p25, minocycline did not have wide effects on tau pathology with only one phospho-epitope showing reduction with treatment (S212/S214). The sum of these findings shows that reduction of the inflammatory events in an AD mouse model prevents cognitive deficits associated with pathology, but that endogenous Aβ-derived neuroinflammation does not contribute significantly to the development of tau pathology. Show more

Keywords: Alzheimer's disease, cognition, inflammation, p25, tau phosphorylation, therapeutic

DOI: 10.3233/JAD-2010-100204

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 527-542, 2010

Authors: Yeh, Po-An | Chang, Ching-Jin | Tu, Pong-Hsien | Wilson, Harry Iain | Chien, Ju-Yi | Tang, Chiou-Yang | Su, Ming-Tsan

Article Type: Research Article

Abstract: The microtubule-associated tau protein has long been considered an axon-specific protein. Although many articles describe the subcellular localization of tau as regulated by post-modification in cultured cells, the intracellular regulation of its distribution in living animals has yet to be elucidated. In the present study, we demonstrate that phosphorylation alters tau polarity in Drosophila melanogaster. Interestingly, it was observed that expression of phosphorylation-incompetent tau impaired neurite growth more severely than either hyperphosphorylated or pseudophosphorylated tau. We also found that inducible expression of hyper- or pseudo-phosphorylated tau in adult flies strikingly prolonged their lifespan. This study offers an alternative tauopathic model …by demonstrating that hyperphosphorylated tau has a beneficial effect on the nervous system. This is also corroborated by common effects seen in a variety of organisms in response to various stresses. We hope that this important animal model leads to a paradigm shift in thinking about hyperphosphorylated tau, which plays a protective role in nervous systems rather than the toxic role that many have historically been given to it. Show more

Keywords: Alzheimer's disease, animal model, Drosophila, lifespan, neuroprotection, PP2A, protein localization, tau phosphorylation, tubulin polymerization

DOI: 10.3233/JAD-2010-091678

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 543-556, 2010

Authors: Alegret, Montserrat | Vinyes-Junqué, Georgina | Boada, Mercè | Martínez-Lage, Pablo | Cuberas, Gemma | Espinosa, Ana | Roca, Isabel | Hernández, Isabel | Valero, Sergi | Rosende-Roca, Maitée | Mauleón, Ana | Becker and, James T. | Tárraga, Lluís

Article Type: Research Article

Abstract: Visuoperceptual processing is impaired early in the clinical course of Alzheimer's disease (AD). The 15-Objects Test (15-OT) detects such subtle performance deficits in mild cognitive impairment (MCI) and mild AD. Reduced brain perfusion in the temporal, parietal, and prefrontal regions have been found in early AD and MCI patients. The objectives of this study were to confirm the role of the 15-OT in the diagnosis of MCI and AD and to investigate the brain perfusion correlates of visuoperceptual dysfunction (15-OT) in subjects with MCI, AD, and normal aging. Forty-two AD, 42 MCI, and 42 healthy elderly control subjects underwent a …brain Single Photon Emission Tomography (SPECT) and separately completed the 15-OT. An analysis of variance compared 15-OT scores between groups. SPM5 was used to analyse the SPECT data. 15-OT performace was impaired in the MCI and AD patients. In terms of the SPECT scans, AD patients showed reduced perfusion in temporal-parietal regions, while the MCI subjects had decreased perfusion in the middle and posterior cingulate. When MCI and AD groups were compared, a significant brain perfusion reduction was found in temporo-parietal regions. In the whole sample, 15-OT performance was significantly correlated with the clinical dementia rating scores, and with the perfusion in the bilateral posterior cingulate and the right temporal pole, with no significant correlation in each separate group. Our findings suggest that the 15-OT performance provides a useful gradation of impairment from normal aging to AD, and it seems to be related to perfusion in the bilateral posterior cingulate and the right temporal pole. Show more

Keywords: Alzheimer's disease, brain SPECT, cerebral perfusion, mild cognitive impairment, visuoperception

DOI: 10.3233/JAD-2010-091069

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 557-567, 2010

Authors: van Eijk, Jeroen J.J. | van Everbroeck, Bart | Abdo, W. Farid | Kremer, Berry P.H. | Verbeek, Marcel M.

Article Type: Research Article

Abstract: In this study we investigated the cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and heavy chain (NFHp35), total tau (t-tau), and glial fibrillary acidic protein (GFAP) to detect disease specific profiles in sporadic Creutzfeldt Jakob disease (sCJD) patients and Alzheimer's disease (AD) patients. CSF levels of NFL, NFHp35, t-tau, and GFAP of 23 sCJD patients and 55 AD patients were analyzed and compared to non-demented controls. Median NFL, NFHp35, GFAP, and t-tau levels were significantly increased in sCJD patients and AD patients versus controls (p < 0.0001 in all). NFL, NFHp35, and t-tau levels were significantly increased in sCJD …patients versus AD patients (p < 0.005), but GFAP concentrations did not differ between sCJD and AD. The results suggest that neuroaxonal damage, reflected by higher CSF levels of NFL, NFHp35, and t-tau, is more pronounced in the pathophysiology of sCJD than in AD. The comparable CSF GFAP concentrations suggest that astroglial damage or astrocytosis is equally pronounced in the pathophysiology of AD and sCJD. Prospective studies are needed to determine whether NFL and NFHp35 may be additional tools in the differential diagnosis of rapidly progressive dementias. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, Creutzfeldt-Jakob disease, diagnosis, prion disease

DOI: 10.3233/JAD-2010-090649

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 569-576, 2010

Authors: Eriksson, Ulrika K. | Sjöberg, Beatrice G. | Bennet, Anna M. | de Faire, Ulf | Pedersen, Nancy L. | Frostegård, Johan

Article Type: Research Article

Abstract: Phosphorylcholine (PC) may play an important role in the atherogenic and pro-inflammatory effects of oxidized low density lipoproteins. We recently demonstrated that low levels of IgM antibodies against PC (anti-PC) are associated with development of myocardial infarction and stroke. We here evaluate the association between anti-PC and dementia and Alzheimer's disease (AD). We conducted a nested case-control study of 182 incident dementia cases (serum collected before onset of dementia) matched to 366 controls and a case-control study of 97 prevalent dementia cases (serum collected after dementia onset) matched to 205 controls. Controls were matched on gender and age at blood …draw (± 1 year). Participants were from the Swedish Twin Registry. Anti-PC levels were measured by ELISA. The odds ratio (OR) of dementia was modeled using conditional logistic regression. Patients with dementia had significantly lower mean anti-PC levels than controls (39.1 versus 49.5 U/ml). The likelihood of having dementia or AD was doubled for individuals with the lowest 25% anti-PC levels (OR=2.04 and 2.70, respectively). The results were similar after adjustments for potential confounders. There was no association between anti-PC levels and incident dementia. Low levels of atheroprotective anti-PC could play a role in AD and dementia. Potential mechanisms include decreased anti-inflammatory potential and effects on the vasculature. Further attention is merited to elucidate the role of anti-PC in AD development and the usefulness of anti-PC as a part of risk prediction, prognosis, diagnosis, or treatment. Show more

Keywords: Alzheimer's disease, dementia, natural antibodies, oxidized LDL, phosphorylcholine

DOI: 10.3233/JAD-2010-091705

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 577-584, 2010

Authors: Güntert, Andreas | Campbell, James | Saleem, Muzamil | O'Brien, Darragh P. | Thompson, Andrew J. | Byers, Helen L. | Ward, Malcolm A. | Lovestone, Simon

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder where definite diagnosis can only be made postmortem, and for which the most promising peripheral markers of disease state and severity have been found in the cerebrospinal fluid. However, recent results suggest that differences in the levels of certain plasma proteins do exist between AD patients and non-demented controls (NDC). Herein, we undertook an untargeted discovery study using isobaric mass tagging to compare the plasma protein levels between slow cognitive declining AD patients, rapid cognitive declining AD patients (RCD) and NDC subjects. Subsequent relative quantification and statistical analysis identified a list of …candidate proteins able to distinguish RCD from NDC groups based on multivariate analysis. Selected proteins were then validated by western blot analysis in an independent sample set of 60 AD and 35 NDC subjects. In this cohort, AD patients displayed significantly lower plasma gelsolin levels compared to NDC subjects. Additionally, gelsolin levels correlated with disease progression rate estimated by Mini-Mental Status Examination decline per year. In order to further investigate gelsolin expression, three different brain regions from an additional cohort of 23 subjects and their respective plasma samples were analysed. No significant change in brain gelsolin levels could be established between AD and control subjects. Interestingly, this study reveals yet another condition where plasma gelsolin levels are decreased and our findings, together with the reported interaction of gelsolin and amyloid-β, makes plasma gelsolin an attractive candidate for further studies targeted at better understanding disease progression in AD. Show more

Keywords: Alzheimer's disease, biomarker, disease progression, mass spectrometry, plasma gelsolin

DOI: 10.3233/JAD-2010-100279

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 585-596, 2010

Authors: Wang, Hongmei | Ma, Jianfang | Tan, Yuyan | Wang, Zhiquan | Sheng, Chengyu | Chen, Shengdi | Ding, Jianqing

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder initiated by the aggregation of amyloid-β peptide (Aβ). Macroautophagy, which is essential for cell survival as well as the promotion of cell death, has been observed extensively in AD brains or transgenic mice overexpressing Aβ protein precursor. However, the role of macroautophagy in the pathogenesis of AD is unclear. In this study, we showed that Aβ1-42 triggered autophagic cell death in both human glioma cell line (U87 cell) and human neuroblastoma cell line (SH-SY5Y cell). Aβ1-42 -induced cytotoxicity and autophagic cell death were blocked by the autophagy inhibitor 3-methyladenine (3-MA) or by …small interfering RNA against the autophagy gene Beclin-1. Reactive oxygen species (ROS) accumulation was also detected in both Aβ1-42 treated cell lines and this accumulation was not affected by 3-MA. Moreover, pretreatment with the ROS scavenger N-acetylcysteine inhibited ROS accumulation and autophagic cell death induced by Aβ1-42 , suggesting that Aβ1-42 -induced ROS accumulation might trigger the onset of autophagy and subsequent autophagic cell death. These findings provide further insights into the mechanisms underlying Aβ-induced cytotoxicity. Show more

Keywords: Apoptosis, autophagic cell death, Beclin-1, N-acetylcysteine, reactive oxygen species

DOI: 10.3233/JAD-2010-091207

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 597-610, 2010

Authors: Hyttinen, Laura | Tuulio-Henriksson, Annamari | Vuorio, Alpo F. | Kuosmanen, Noora | Härkänen, Tommi | Koskinen, Seppo | Strandberg, Timo E.

Article Type: Research Article

Abstract: The cognitive status of aged familial hypercholesterolemia (FH) patients treated with long-term statin therapy was compared with that of population controls. A comprehensive cohort of 43 elderly (age ⩾ 65 years) patients all with the same FH North Karelia mutation living in North Karelia (eastern Finland) was identified, 37 of whom (aged 65 to 84 years) agreed to participate. All but one of these FH patients had been using statins for approximately 15 years. Population-based controls (aged 65 to 84 years, n= 309) were the participants of the Health 2000 Survey living in eastern Finland. The cognitive assessment was conducted …with tests for verbal fluency, Word List Learning (WLL) and Word List Delayed Recall (WLDR) subtests in the Consortium to Establish a Registry for Alzheimer's disease test battery. After adjustment for age, gender, education, diabetes mellitus, and coronary heart disease, FH patients were more likely to be in the top tertile of the WLDR (Odds ratio (OR) 3.40, 95% confidence interval (CI) 1.52–7.63) and WLL3 (OR 2.83, 95% CI 1.28–6.25) subtests. When the FH patients were subdivided according to the median length of their statin therapy, the ORs to be in the top tertile in the WLDR subtest were 1.65 (95% CI 0.52–5.25) for those with less and 5.40 (95% CI 1.74–17.72) in those individuals with more than median length of statin therapy. In conclusion, aged FH patients receiving long-term statin therapy exhibited better episodic memory than population controls, and this association became even more pronounced with longer statin therapy. Show more

Keywords: Aged, CERAD, familial hypercholesterolemia, statins

DOI: 10.3233/JAD-2010-091381

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 611-617, 2010

Authors: Rodrıguez-Rodrıguez, Eloy | Vázquez-Higuera, José Luis | Sánchez-Juan, Pascual | Mateo, Ignacio | Pozueta, Ana | Martínez-García, Ana | Frank, Ana | Valdivieso, Fernando | Berciano, José | Bullido, María J. | Combarros, Onofre

Article Type: Research Article

Abstract: Aberrant cholesterol metabolism has been implicated in Alzheimer's disease (AD). Recent findings have suggested an interaction of Niemann-Pick C1 (NPC1) and ATP-binding cassette transporter A1 (ABCA1) proteins in intracellular cholesterol transport and in maintaining cell cholesterol balance. Underexpression of NPC1 in concert with under-expression of ABCA1 would result in increased cholesterol accumulation and increased AD risk. We examined a functional polymorphism in the ABCA1 promoter region (-477, rs2422493), and four NPC1 polymorphisms in exon 6 (rs18050810), intron 20 (rs4800488), intron 22 (rs2236707), and intron 24 (rs2510344) capturing 85% of genetic variability in the Hap Map Caucasian (CEU) population, in a …group of 631 Spanish AD patients and 731 controls. Subjects carrying both the ABCA1 (-477) TT genotype and the NPC1 (exon 6) GG genotype (OR=1.89; 95% CI 1.04–3.41), NPC1 (intron 20) AA genotype (OR=2.05; 95% CI 1.26–3.33), NPC1 (intron 22) AA genotype (OR=2.05; 95% or NPC1 (intron 24) GG genotype (OR=1.89; 95% higher risk of developing AD than subjects without these risk genotypes. Testing for epistatic interaction between genes in the pathway of cholesterol metabolism might be useful for predicting AD risk. Show more

Keywords: ABCA1, Alzheimer's disease, cholesterol, epistasis, NPC1, polymorphism

DOI: 10.3233/JAD-2010-100432

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 619-625, 2010

Authors: Serra, Laura | Perri, Roberta | Cercignani, Mara | Spanò, Barbara | Fadda, Lucia | Marra, Camillo | Carlesimo, Giovanni A. | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: Behavioral and psychological symptoms of dementia (BPSD) are commonly observed over the course of Alzheimer's disease (AD). However, it is unclear whether BPSD are part of AD neuropathology or rather represent a psychological reaction to cognitive disabilities. Using voxel-based-morphometry (VBM), we aimed to clarify this issue by investigating patients with AD at different clinical stages. Twenty-seven patients with AD (12 early [ADe] and 15 moderate [ADm]), 19 with amnestic mild cognitive impairment (a-MCI), and 23 healthy controls underwent MRI scanning at 3T. Assessment of BPSD was done in each patient using the Neuropsychiatric Inventory-12 (NPI-12). VBM was used to investigate …changes in grey matter (GM) atrophy across groups, and associations between regional GM volumes and occurrence and severity of BPSD in patients. Mood disorders, anxiety, and agitation were present in both a-MCI and AD, while psychotic symptoms were observed mainly in AD. As expected, VBM showed only limited areas of GM atrophy in a-MCI patients, with a progressive extension in ADe and ADm patients (PFWE -corrected-values < 0.05). Disinhibition was strongly associated with GM volume in bilateral cingulate and right middle frontal gyri, while delusions were associated with GM volume in right hippocampus (PFWE -corrected-values < 0.05). This study confirms that BPSD are present since the earliest AD stages. Interesting associations were found in regions traditionally implicated by AD neuropathology. This suggests that BPSD are likely to represent clinical features of AD and should be regarded for their diagnostic and prognostic value. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, behavioral and psychological symptoms of dementia (BPSD), neurodegeneration, NPI-12, voxel-based morphometry

DOI: 10.3233/JAD-2010-100048

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 627-639, 2010

Authors: Sedaghat, Fereshteh | Dedousi, Eleni | Baloyannis, Ioannis | Tegos, Thomas | Costa, Vasiliki | Dimitriadis, Athanasios S. | Baloyannis, Stavros J.

Article Type: Research Article

Abstract: Anosognosia is a common symptom of dementia. The aim of this study was to evaluate the contribution of different regions of the brain to anosognosia in Alzheimer's disease (AD) brains using single photon emission computed tomography (SPECT). Forty-two patients with AD were included in this study. After clinical interviews with the patients and their relatives, the patients were divided into two groups: Anosognosia and No-anosognosia. The patients were studied regarding the severity of dementia. They underwent SPECT with HMPAO and regional cerebral blood flow (rCBF) was measured. Regional CBF significantly differed between Anosognosia and No-anosognosia groups in right prefrontal (P …⩽ 0.02), right inferior parietal (P ⩽ 0.00), and right (P ⩽ 0.01) and left (P ⩽ 0.01) medial temporal cortex. There was a significant correlation between the severity of dementia and rCBF in medial temporal regions. When comparisons were made between mild and moderate stages separately, the 'right inferior parietal region' was the common region which showed hypoperfusion in both anosognosia subgroups. We conclude that anosognosia may be a reflection of functional impairment in right prefrontal, right frontal and especially right inferior parietal regions in AD. Show more

Keywords: Alzheimer, anosognosia, brain SPECT, disease unawareness, right parietal, right prefrontal

DOI: 10.3233/JAD-2010-090631

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 641-647, 2010

Authors: Arrieta-Cruz, Isabel | Wang, Jun | Pavlides, Constantine | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: In this study, we examined acute effects of carvedilol, a nonselective α/β-adrenergic receptor blocker, on neuronal transmission and long-term potentiation (LTP) in six month-old TgCRND8 mice and their wild-type age-matched controls. Field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus from carvedilol- or vehicle dimethyl sulfoxide-treated slices, and differences in basal synaptic transmission and LTP were assessed. Carvedilol treatment produced a significant increase in basal synaptic transmission and LTP in TgCRND8 mice, as compared to their vehicle-treated slices, in which basal neuronal transmission and LTP decreased. Interestingly, carvedilol significantly suppressed spontaneous seizure activity in TgCRND8 mice …as measured by the number of slices showing epileptic discharges as well as the number of spikes within these and the amplitude of the second spike, measured at baseline and end of recording. In contrast, vehicle-treated slices in TgCRND8 mice did not show a significant decrease in epileptic discharges. These results suggest that carvedilol reestablishes basal synaptic transmission, enhances neuronal plasticity and suppresses neuronal hyperexcitability in TgCRND8 mice. Show more

Keywords: Alzheimer's disease, carvedilol, epileptic discharges, hippocampus, LTP, neuronal transmission, synaptic plasticity, TgCRND8 mice

DOI: 10.3233/JAD-2010-100225

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 649-654, 2010

Authors: Liu, Shi-Jie | Gasperini, Robert | Foa, Lisa | Small, David Henry

Article Type: Research Article

Abstract: α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are key regulators of synaptic function and cognition. In Alzheimer's disease (AD), cell-surface AMPARs are downregulated, however the reason for this downregulation is not clear. In the present study, we found that Aβ significantly decreased levels of the cell-surface AMPA-type glutamate receptor subunit 2 (GluR2), and increased the concentration of free cytosolic calcium ion ([Ca2+ ]i ) in hippocampal neurons. Ion channel blockers (nifedipine, tetrodotoxin, SKF96365) decreased [Ca2+ i and increased the level of cell-surface GluR2, whereas Bay K 8644, an activator of L-type voltage-gated calcium channels increased [Ca2+ ]i and decreased cell-surface GluR2. …Aβ and Bay K 8644 increased phosphorylation of serine-880 (S880) on GluR2, whereas the nifedipine. tetrodotoxin and SKF96365 decreased S880 phosphorylation. Finally, we found that bisindolylmeimide I (GF 109203X, GFX), an inhibitor of protein kinase C (PKC) blocked both the decrease in cell-surface GluR2 and the increase in phospho-S880 induced by Aβ and Bay K 8644. Taken together, these results demonstrate that Aβ decreases cell-surface GluR2 by increasing PKC-mediated phosphorylation of S880. Our study supports the view that a rise in cytosolic [Ca2+ ]i induced by Aβ could impair synaptic function by decreasing the availability of AMPARs at the synapse. This decrease in AMPARs may contribute to the decline in cognitive function seen in AD. Show more

Keywords: Alzheimer's disease, AMPA, amyloid-β, calcium, GluR2, phospho-GluR2, PKC

DOI: 10.3233/JAD-2010-091654

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 655-666, 2010

Authors: Fagan, Tom

Article Type: Research Article

DOI: 10.3233/JAD-2010-101340

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 667-671, 2010