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

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