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