Journal of Alzheimer's Disease - Volume 54, issue 2

Authors: Beckelman, Brenna C. | Day, Stephen | Zhou, Xueyan | Donohue, Maggie | Gouras, Gunnar K. | Klann, Eric | Keene, C. Dirk | Ma, Tao

Article Type: Research Article

Abstract: Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer’s disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in …AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets. Show more

Keywords: Alzheimer’s disease, elongation factor, long-term potentiation, mTOR, protein synthesis, synaptic plasticity

DOI: 10.3233/JAD-160036

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 669-678, 2016

Authors: Yu, Qing | Fang, Du | Swerdlow, Russell Howard | Yu, Haiyang | Chen, John Xi | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Mitochondrial dysfunction and axonal degeneration are early pathological features of Alzheimer’s disease (AD)-affected brains. The underlying mechanisms and strategies to rescue it have not been well elucidated. Here, we evaluated axonal mitochondrial transport and function in AD subject-derived mitochondria. We analyzed mitochondrial transport and kinetics in human trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells whose mitochondria were derived from platelets of patients with sporadic AD and compared these AD cybrid cell lines with cybrid cell lines whose mitochondria were derived from age-matched, cognitively normal subjects. Human AD cybrid cell lines, when induced to differentiate, developed stunted projections. Mitochondrial transport and function …within neuronal processes/axons was altered in AD-derived mitochondria. Antioxidants reversed deficits in axonal mitochondrial transport and function. These findings suggest that antioxidants may be able to mitigate the consequences of AD-associated mitochondrial dysfunction. The present study provides evidence of the cause/effect of AD specific mitochondrial defects, which significantly enhances our understanding of the AD pathogenesis and exploring the effective therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, antioxidants, cybrid cells, mitochondrial dysfunction, mitochondrial transport

DOI: 10.3233/JAD-160532

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 679-690, 2016

Authors: Klafki, Hans-W. | Hafermann, Henning | Bauer, Chris | Haussmann, Ute | Kraus, Inga | Schuchhardt, Johannes | Muck, Stephan | Scherbaum, Norbert | Wiltfang, Jens

Article Type: Research Article

Abstract: A comprehensive assay validation campaign of a commercially available chemiluminescence multiplex immunoassay for the simultaneous measurement of the amyloid-β peptides Aβ38 , Aβ40 , and Aβ42 in human cerebrospinal fluid (CSF) is presented. The assay quality parameters we addressed included impact of sample dilution, parallelism, lower limits of detection, lower limits of quantification, intra- and inter-assay repeatability, analytical spike recoveries, and between laboratory reproducibility of the measurements. The assay performed well in our hands and fulfilled a number of predefined acceptance criteria. The CSF levels of Aβ40 and Aβ42 determined in a clinical cohort (n  = 203) were …statistically significantly correlated with available ELISA data of Aβ1–40 (n  = 158) and Aβ1–42 (n  = 179) from a different laboratory. However, Bland-Altman method comparison indicated systematic differences between the assays. The data presented here furthermore indicate that the CSF concentration of Aβ40 can surrogate total CSF Aβ and support the hypothesis that the Aβ42 /Aβ40 ratio outperforms CSF Aβ42 alone as a biomarker for Alzheimer’s disease due to a normalization to total Aβ levels. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, assay validation, biomarker, cerebrospinal fluid, multiplex immunoassay

DOI: 10.3233/JAD-160398

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 691-705, 2016

Authors: Hakobyan, Svetlana | Harding, Katharine | Aiyaz, Mohammed | Hye, Abdul | Dobson, Richard | Baird, Alison | Liu, Benjamine | Harris, Claire Louise | Lovestone, Simon | Morgan, Bryan Paul

Article Type: Research Article

Abstract: There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. …Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p  < 10- 5 ). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification. Show more

Keywords: Alzheimer’s disease, biomarker, complement, inflammation

DOI: 10.3233/JAD-160420

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 707-716, 2016

Authors: Cioffi, Sara M.G. | Galimberti, Daniela | Barocco, Federica | Spallazzi, Marco | Fenoglio, Chiara | Serpente, Maria | Arcaro, Marina | Gardini, Simona | Scarpini, Elio | Caffarra, Paolo

Article Type: Research Article

Abstract: Mutations in progranulin gene (GRN ) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence …of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN . Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers. Show more

Keywords: Deletion, frontotemporal dementia, haploinsufficiency, mutation, non-fluent variant primary progressive aphasia, progranulin (GRN), splicing

DOI: 10.3233/JAD-160185

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 717-721, 2016

Authors: Blockx, Ines | Einstein, Steve | Guns, Pieter-Jan | Van Audekerke, Johan | Guglielmetti, Caroline | Zago, Wagner | Roose, Dimitri | Verhoye, Marleen | Van der Linden, Annemie | Bard, Frederique

Article Type: Research Article

Abstract: Background: Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-amyloid-β (Aβ) immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). Although the clinical significance and pathophysiology are unknown, it has been proposed that anti-Aβimmunotherapy may affect blood-brain barrier (BBB) integrity. Objective: To examine vascular integrity in aged (12–16 months) PDAPP and wild type mice (WT), we performed a series of longitudinal in vivo MRI studies. Methods: Mice were treated on a weekly basis using anti-Aβimmunotherapy (3D6) and follow up was …done longitudinally from 1–12 weeks after treatment. BBB-integrity was assessed using both visual assessment of T1 -weighted scans and repeated T1 mapping in combination with gadolinium (Gd-DOTA). Results: A subset of 3D6 treated PDAPP mice displayed numerous BBB disruptions, whereas WT and saline-treated PDAPP mice showed intact BBB integrity under the conditions tested. In addition, the contrast induced decrease in T1 value was observed in the meningeal and midline area. BBB disruption events occurred early during treatment (between 1 and 5 weeks), were transient, and resolved quickly. Finally, BBB-leakages associated with microhemorrhages were confirmed by Perls’Prussian blue histopathological analysis. Conclusion: Our preclinical findings support the hypothesis that 3D6 leads to transient leakage from amyloid-positive vessels. The current study has provided valuable insights on the time course of vascular alterations during immunization treatment and supports further research in relation to the nature of ARIA and the utility of in vivo repeated T1 MRI as a translational tool. Show more

Keywords: Alzheimer’s disease, amyloid-related imaging abnormalities, blood-brain barrier, immunotherapy, magnetic resonance imaging, neuroimaging, transgenic mouse model

DOI: 10.3233/JAD-160023

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 723-735, 2016

Authors: Luccarini, Ilaria | Pantano, Daniela | Nardiello, Pamela | Cavone, Leonardo | Lapucci, Andrea | Miceli, Caterina | Nediani, Chiara | Berti, Andrea | Stefani, Massimo | Casamenti, Fiorella

Article Type: Research Article

Abstract: Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer’s disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 months) and intermediate (6 months) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-week OLE treatment (50 mg/kg of diet) to 6-month-old TgCRND8 …mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24 h with either OLE (100μM) or PARP inhibitors. A significant reduction of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90 min; the latter was slightly attenuated by cell treatment for 24 h with PJ-34 or with OLE. In vitro and in vivo , the OLE-induced reduction of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo , by a decrease of NF-κ B and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay. Show more

Keywords: Alzheimer’s disease, animal model of Aβ deposition, olive oil polyphenols, PAR polymers

DOI: 10.3233/JAD-160471

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 737-750, 2016

Authors: Pérez-Grijalba, Virginia | Fandos, Noelia | Canudas, Jesús | Insua, Daniel | Casabona, Diego | Lacosta, Ana M. | Montañés, María | Pesini, Pedro | Sarasa, Manuel

Article Type: Research Article

Abstract: Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer’s disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-β (Aβ) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident interpretation of clinical results. The aim of this study was to validate ELISA sandwich colorimetric ABtest40 and ABtest42 for the quantification of Aβ40 and Aβ42 in human plasma. …The validation parameters assessed included precision, accuracy, sensitivity, specificity, recovery, and dilution linearity. ABtest40 and ABtest42 proved to be specific for their target peptide using Aβ peptides with sequence similar to the target. Mean relative error in the quantification was found to be below 7.5% for both assays, with high intra-assay, inter-assay, and inter-batch precision (CV <9.0% on average). Sensitivity was assessed by determination of the limit of quantification fulfilling precision and accuracy criteria; it was established at 7.60 pg/ml and 3.60 pg/ml for ABtest40 and ABtest42, respectively. Plasma dilution linearity was demonstrated in PBS; however, dilution in a proprietary formulated buffer significantly increased the recovery of both Aβ40 and Aβ42 masked by matrix interactions, allowing a more comprehensive assessment of the free and total peptide levels in the plasma. In conclusion, both assays were successfully validated as tools for the quantification Aβ40 and Aβ42 in plasma. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, biomarker, immunoassay validation, plasma

DOI: 10.3233/JAD-160325

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 751-762, 2016

Authors: Morozov, Alexey V. | Kulikova, Alexandra A. | Astakhova, Tatiana M. | Mitkevich, Vladimir A. | Burnysheva, Ksenia M. | Adzhubei, Alexei A. | Erokhov, Pavel A. | Evgen’ev, Michail B. | Sharova, Natalia P. | Karpov, Vadim L. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Accumulation of amyloid-β (Aβ) in neurons accompanies Alzheimer’s disease progression. In the cytoplasm Aβ influences activity of proteasomes, the multisubunit protein complexes that hydrolyze the majority of intracellular proteins. However, the manner in which Aβ affects the proteolytic activity of proteasomes has not been established. In this study the effect of Aβ42 and Aβ42 with isomerized Asp7 on activity of different forms of proteasomes has been analyzed. It has been shown that Aβ peptides efficiently reduce activity of the 20S proteasomes, but increase activity of the 20S proteasomes capped with the 19S and/or 11S regulators. Modulation of proteasome …activity is mainly determined by the C-terminal segment of Aβ (amino acids 17-42). This study demonstrated an important role of proteasome regulators in the interplay between Aβ and the proteasomes. Show more

Keywords: Keywords: Alzheimer’s disease, amyloid-β, 20S proteasome, 19S regulator particle, 11S regulator

DOI: 10.3233/JAD-160491

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 763-776, 2016

Authors: Lozano, Andres M. | Fosdick, Lisa | Chakravarty, M. Mallar | Leoutsakos, Jeannie-Marie | Munro, Cynthia | Oh, Esther | Drake, Kristen E. | Lyman, Christopher H. | Rosenberg, Paul B. | Anderson, William S. | Tang-Wai, David F. | Pendergrass, Jo Cara | Salloway, Stephen | Asaad, Wael F. | Ponce, Francisco A. | Burke, Anna | Sabbagh, Marwan | Wolk, David A. | Baltuch, Gordon | Okun, Michael S. | Foote, Kelly D. | McAndrews, Mary Pat | Giacobbe, Peter | Targum, Steven D. | Lyketsos, Constantine G. | Smith, Gwenn S.

Article Type: Research Article

Abstract: Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD). Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Results: Surgery and electrical …stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n  = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n  = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation. Show more

Keywords: Keywords: Alzheimer’s disease, dementia, deep brain stimulation, fornix

DOI: 10.3233/JAD-160017

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 777-787, 2016

Authors: Fried, Itzhak

Article Type: Article Commentary

Abstract: Deep brain stimulation has been successfully used in treatment of motor symptoms of Parkinson’s disease and other movement disorders. In a recent multi-center prospectively randomized study, deep brain stimulation of the fornix was administered in order to ameliorate the cognitive symptoms and clinical course of Alzheimer’s disease (AD). The study points to the possibility of modest slowing of the cognitive decline in AD in a subset of patients older than 65, while at the same time highlights the risk of stimulation in exacerbation of this decline in younger patients. The logic of conducting large clinical trials in the face of …limited scientific understanding of the pathophysiology of AD and response of affected brain regions to electrical stimulation, is discussed with emphasis on the need to conduct: (i) animal studies in AD models, using precise focused stimulation; (ii) studies in patients who are implanted with depth electrodes for established clinical reasons (i.e., patients with epilepsy or movement disorders); and (iii) smaller adaptive studies in AD patients with systematic alterations of therapeutic parameters such as stimulation protocol. Show more

Keywords: Alzheimer’s disease, dementia, deep brain stimulation, fornix, hippocampus, entorhinal area

DOI: 10.3233/JAD-160719

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 789-791, 2016

Authors: Curiel, Rosie E. | Crocco, Elizabeth | Rosado, Marian | Duara, Ranjan | Greig, Maria T. | Raffo, Arlene | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer’s disease research. Objective: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community. Methods: Participants that were CN (n  = 64) or MCI (n  = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument …is a brief, computerized paired associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity. Results: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L. Conclusions: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research. Show more

Keywords: Alzheimer’s disease, computerized tests, memory, mild cognitive impairment, MITSI-L

DOI: 10.3233/JAD-160370

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 793-799, 2016

Authors: Gomm, Willy | von Holt, Klaus | Thomé, Friederike | Broich, Karl | Maier, Wolfgang | Weckbecker, Klaus | Fink, Anne | Doblhammer, Gabriele | Haenisch, Britta

Article Type: Research Article

Abstract: Background: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing. Objective: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set. Methods: Using longitudinal German public health insurance data …from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. Results: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13–1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed. Conclusion: The restricted use of BDZRs may contribute to dementia prevention in the elderly. Show more

Keywords: Benzodiazepines, dementia, elderly, risk factor, z-substances

DOI: 10.3233/JAD-151006

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 801-808, 2016

Authors: Khmeleva, Svetlana A. | Radko, Sergey P. | Kozin, Sergey A. | Kiseleva, Yana Y. | Mezentsev, Yuri V. | Mitkevich, Vladimir A. | Kurbatov, Leonid K. | Ivanov, Alexis S. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ) plays a central role in Alzheimer’s disease (AD) pathogenesis. Besides extracellular Aβ, intraneuronal Aβ (iAβ) has been suggested to contribute to AD onset and development. Based on reported in vitro Aβ-DNA interactions and nuclear localization of iAβ, the interference of iAβ with the normal DNA expression has recently been proposed as a plausible pathway by which Aβ can exert neurotoxicity. Employing the sedimentation assay, thioflavin T fluorescence, and dynamic light scattering we have studied effects of zinc ions on binding of RNA and single- and double-stranded DNA molecules to Aβ42 aggregates. It has been found …that zinc ions significantly enhance the binding of RNA and DNA molecules to pre-formed β-sheet rich Aβ42 aggregates. Another type of Aβ42 aggregates, the zinc-induced amorphous aggregates, was demonstrated to also bind all types of nucleic acids tested. To evaluate the role of the Aβ metal-binding domain’s histidine residues in Aβ-nucleic acid interactions mediated by zinc, Aβ16 mutants with substitutions H6R and H6A-H13A and rat Aβ16 lacking histidine residue 13 were used. The zinc-induced interaction of Aβ16 with DNA was shown to critically depend on histidine residues 6 and 13. However, the inclusion of H6R mutation in Aβ42 peptide did not affect DNA binding to Aβ42 aggregates. Since oxidative and/or nitrosative stresses implicated in AD pathogenesis are known to release zinc ions from metallothioneins in cytoplasm and cell nuclei, our findings suggest that intracellular zinc can be an important player in iAβ-nucleic acid interactions. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, DNA, histidine residues, RNA, zinc

DOI: 10.3233/JAD-160415

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 809-819, 2016

Authors: Selivanova, Olga M. | Surin, Alexey K. | Marchenkov, Victor V. | Dzhus, Ulyana F. | Grigorashvili, Elizaveta I. | Suvorina, Mariya Yu. | Glyakina, Anna V. | Dovidchenko, Nikita V. | Galzitskaya, Oxana V.

Article Type: Research Article

Abstract: It has been demonstrated using Aβ40 and Aβ42 recombinant and synthetic peptides that their fibrils are formed of complete oligomer ring structures. Such ring structures have a diameter of about 8-9 nm, an oligomer height of about 2– 4 nm, and an internal diameter of the ring of about 3-4 nm. Oligomers associate in a fibril in such a way that they interact with each other, overlapping slightly. There are differences in the packing of oligomers in fibrils of recombinant and synthetic Aβ peptides. The principal difference is in the degree of orderliness of ring-like oligomers that leads to generation of …morphologically different fibrils. Most ordered association of ring-like structured oligomers is observed for a recombinant Aβ40 peptide. Less ordered fibrils are observed with the synthetic Aβ42 peptide. Fragments of fibrils the most protected from the action of proteases have been determined by tandem mass spectrometry. It was shown that unlike Aβ40 , fibrils of Aβ42 are more protected, showing less ordered organization compared to that of Aβ40 fibrils. Thus, the mass spectrometry data agree with the electron microscopy data and structural models presented here. Show more

Keywords: Aβ42 and Aβ40 peptides, Alzheimer’s disease, amyloid fibrils, polymorphism, ring-like oligomers

DOI: 10.3233/JAD-160405

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 821-830, 2016

Authors: Zimova, Ivana | Brezovakova, Veronika | Hromadka, Tomas | Weisova, Petronela | Cubinkova, Veronika | Valachova, Bernadeta | Filipcik, Peter | Jadhav, Santosh | Smolek, Tomas | Novak, Michal | Zilka, Norbert

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151–391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting …of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy. Show more

Keywords: Alzheimer’s disease, neurofibrillary degeneration, tauopathies, transgenic mouse, truncated tau protein

DOI: 10.3233/JAD-160347

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 831-843, 2016

Authors: Cestari, José Augusto Ferrari | Fabri, Gisele Maria Campos | Kalil, Jorge | Nitrini, Ricardo | Jacob-Filho, Wilson | Tesseroli de Siqueira, José Tadeu | Siqueira, Silvia Regina D.T.

Article Type: Correction

DOI: 10.3233/JAD-169006

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 845-845, 2016

Article Type: Other

DOI: 10.3233/JAD-160728

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 847-852, 2016