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