Journal of Alzheimer's Disease - Volume 21, issue 4

Authors: Palotás, András | Reis, Helton J. | Bogáts, Gábor | Babik, Barna | Racsmány, Mihály | Engvau, Linda | Kecskeméti, Éva | Juhász, Anna | Vieira, Luciene B. | Teixeira, Antônio L. | Mukhamedyarov, Marat A. | Rizvanov, Albert A. | Yalvaç, Mehmet E. | Guimarães, Melissa M. | Ferreira, Cláudia N. | Zefirov, Andrey L. | Kiyasov, Andrey P. | Wang, Lan | Janka, Zoltán | Kálmán, János

Article Type: Research Article

Abstract: Several biomarkers are used in confirming the diagnosis of cognitive disorders. This study evaluates whether the level of these markers after heart surgery correlates with the development of cognitive dysfunction, which is a frequent complication of cardiac interventions. Concentrations of amyloid-β peptide, tau, and S100β in the cerebro-spinal fluid were assessed, as well as cognitive functions were evaluated before and after coronary artery bypass grafting, utilizing immuno-assays and psychometric tests, respectively. A drastic rise in the level of S100β was observed one week after the surgery, a mark of a severe generalized cerebral injury. The level of amyloid-β peptide significantly …decreased, whereas the concentration of tau markedly increased six months postoperatively. Gradual cognitive decline was also present. These findings clearly demonstrate post-surgical cognitive impairment associated with changes in biomarkers similar to that seen in Alzheimer's disease, suggesting a unifying pathognomic factor between the two disorders. A holistic approach to coronary heart disease and Alzheimer's-type dementia is proposed. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, biomarker, cardiac surgery, cerebrospinal fluid, cognitive function, postoperative cognitive decline, S100β, tau

DOI: 10.3233/JAD-2010-100702

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1153-1164, 2010

Authors: Baldeiras, Inês | Santana, Isabel | Proença, Maria Teresa | Garrucho, Maria Helena | Pascoal, Rui | Rodrigues, Ana | Duro, Diana | Oliveira, Catarina Resende

Article Type: Research Article

Abstract: Recent studies show that most of the oxidative changes found in Alzheimer's disease (AD) are already present in mild cognitive impairment (MCI) patients. The question arises as to whether oxidative stress has a role in the progression of MCI to AD. We conducted a longitudinal study on 70 MCI patients, and the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species were determined. At baseline, there were no differences in any of the indexes of oxidative damage between stable MCI patients (MCI-MCI) and patients …that progressed to AD (MCI-AD). Cellular levels of lipid peroxidation markers increased in both groups and this was accompained in MCI-AD, but not in MCI-MCI patients, by a significant decrease in cellular antioxidant defenses (oxidyzed/reduced glutathione ratio and vitamin E). Among MCI-AD patients, the longitudinal decrease in cellular vitamin E was associated with the deterioration in cognitive performance. These results suggest that accumulation of oxidative damage may start in pre-symptomatic phases of AD pathology and that progression to AD might be related to depletion of antioxidant defenses. Show more

Keywords: Alzheimer's disease, antioxidants, longitudinal, mild cognitive impairment, oxidative stress

DOI: 10.3233/JAD-2010-091723

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1165-1177, 2010

Authors: Panza, Francesco | Solfrizzi, Vincenzo | Seripa, Davide | Imbimbo, Bruno P. | Pilotto, Alberto | Frisardi, Vincenza

Article Type: Article Commentary

Abstract: Mild cognitive impairment (MCI) is recognized as a prodromal phase of dementing disorders, and it has been suggested that oxidative stress may play a role in the pathogenesis of Alzheimer's disease (AD), and in predicting progression of MCI to AD. In the present article, on the basis of an increasing body of evidence from cross-sectional and longitudinal studies, we discussed the issue of the possible impact of antioxidant compounds from diet and supplementation on MCI and its progression to AD.

Keywords: Alzheimer's disease, dementia, mild cognitive impairment, oxidative stress, vascular dementia

DOI: 10.3233/JAD-2010-101224

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1179-1183, 2010

Authors: Blanchard, Julie | Chohan, Muhammad Omar | Li, Bin | Liu, Fei | Iqbal, Khalid | Grundke-Iqbal, Inge

Article Type: Research Article

Abstract: A therapeutic strategy against cognitive disorders like Alzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic factors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic factor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skeletal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147–150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition …without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuronal commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal-dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition. Show more

Keywords: Cognition, ciliary neurotrophic factor, dendritic and synaptic plasticity, dentate gyrus, leukemia inhibitory factor signalling

DOI: 10.3233/JAD-2010-1000069

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1185-1195, 2010

Authors: Thanh Nam, Dang | Arseneault, Madeleine | Zarkovic, Neven | Waeg, Georg | Ramassamy, Charles

Article Type: Research Article

Abstract: Acrolein is the most reactive aldehyde among the by-products of lipid peroxidation. Growing evidence indicates that acrolein may play an important role in the pathogenesis of Alzheimer's disease (AD). In AD, levels of acrolein are significantly higher in hippocampus and temporal cortex regions of the brain. However, little is known about its toxicity in neuronal cells. Using the neuroblastoma cell line SK-N-SH, our results show that acrolein is toxic from 10 μM, but its toxicity does not induce the activation of caspase-3 and DNA fragmentation. Protein carbonylation and 4-hydroxy-nonenal levels were increased after 0.5 hr and 1 hr of treatment, …respectively. Furthermore acrolein induced a biphasic effect on glutathione levels with a rapid depletion followed by a progressive increase. We have further investigated the regulation of different redox signaling pathways. A treatment with 10 μM of acrolein for 30 min activated NFκB while this activation was suppressed after a 24 hrs of treatment. In contrast, Nrf2 was activated only after 24 hrs of acrolein exposure. Consequently, the expression of heme oxygenase-1 and γ-glutamyl-cysteine-synthase were elevated after 24 hrs of acrolein treatment. Sirt-1 was also upregulated after 24 hrs of acrolein treatment. The p66Shc and ERK1/2 proteins are known to be involved in oxidative stress. Acrolein, at 10 μM, induced the phosphorylation of p66Shc and ERK1/2 only after a short period of treatment. Collectively, these data strengthen the contribution of acrolein in the induction of oxidative stress as observed in mild cognitive impairment and in AD brain. Show more

Keywords: Acrolein, Alzheimer disease, lipid peroxidation, oxidative stress

DOI: 10.3233/JAD-2010-100417

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1197-1216, 2010

Authors: Couturier, Julien | Page, Guylène | Morel, Milena | Gontier, Céline | Lecron, Jean-Claude | Pontcharraud, Raymond | Fauconneau, Bernard | Paccalin, Marc

Article Type: Research Article

Abstract: Alzheimer's disease (AD), a neurodegenerative disorder, is the most common form of dementia in the elderly individuals. Among the pathogenic mechanisms in AD, chronic systemic inflammation is described and characterized by massive production of proinflammatory cytokines by peripheral blood mononuclear cells (PBMCs), which may contribute to an altered immune response and exacerbation of neurodegeneration. Studies have also reported increased double-stranded RNA-dependent protein kinase (PKR) activation in the PBMCs of patients with AD. Interestingly, PKR could be involved in NF-κB activation, leading to production of a wide range of cytokines. We proposed to decrease proinflammatory cytokines production and release by treating …the PBMCs in 25 patients with AD with a specific inhibitor of PKR. Our results showed that PKR inhibition greatly decreased tumor necrosis factor α, interleukin (IL)-1α, IL-1β, and IL-6 production and release but did not affect the chemokine RANTES. Moreover, inhibition of the proinflammatory factors was correlated with prevention of caspase-3 activation. These results indicated that specific inhibition of PKR at the peripheral level might decrease the inflammatory response in AD. Show more

Keywords: Alzheimer's disease, apoptosis, blood cells, chemokines, cytokines, NF-κB, protein kinase PKR

DOI: 10.3233/JAD-2010-100258

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1217-1231, 2010

Authors: Li, Zhifang | Gao, Changyue | Huang, Heqing | Sun, Weizhong | Yi, Hongliang | Fan, Xiaotang | Xu, Haiwei

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by the dysfunction or loss of a vulnerable group of neurons. At present, only a few options exist for treating neurodegenerative diseases effectively. Advances in stem cell research have raised the hope and possibility for therapy in neurodegenerative diseases. In AD transgenic animal models, stem cell transplantation has been demonstrated to reverse behavioral deficits. Our recent study demonstrates that neural precursor cells, derived from embryonic stem (ES) cells, improve memory dysfunction in rats caused by injections of amyloid-β peptide (1-40) (Aβ1-40 ) in the dorsal hippocampus. However, the underlying mechanisms remain unknown. The present study …tests a murine ES cell-based transplantation approach in rats subjected to Aβ1-40 injection into the hippocampus dentate gyrus. Efficacy of cell therapy with regard to graft survival, neuronal yield and diversity, synapse formation of the grafted cells, and the behavioral improvements was determined after transplanting ES cell-derived neural precursors into the hippocampus of adult rats. Here, we show that grafted cells can survive, and differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse neurotransmitter-subtypes. More importantly, transplanted cells demonstrate characteristics of proper synapse formation between host and grafted neural cells. Thus, our observations show that an ES cell-based transplantation approach may be promising in the treatment of AD. Show more

Keywords: Alzheimer's disease, embryonic stem cell, neuronal differentiation, synapse formation, transplantation

DOI: 10.3233/JAD-2010-100003

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1233-1247, 2010

Authors: Li, Chenghua | Wang, Juan | Zhou, Bing

Article Type: Research Article

Abstract: Clioquinol (CQ), a once popular antibiotic, was used to inhibit the growth of microorganisms. Recently, CQ and its analog PBT2 have shown encouraging effects in the animal and clinical trials for Alzheimer's disease (AD). However, the mechanism by which this class of molecules works remains controversial. In this work, we used the yeast Saccharomyces cerevisiae as a model to study how CQ affects molecular and cellular functions and particularly, copper, iron, and zinc homeostasis. We observed a CQ-induced inhibition of yeast growth, which could be slightly relieved by supplementation of copper or iron. Microarray results indicated that yeast cells treated …with CQ sense a general deficiency in metals, despite elevated total cellular contents of copper and iron. Consistent with this, reduced activities of some metal-sensitive enzymes were observed. Intriguingly, CQ can increase the SOD1 activity, likely through Ccs1's accessibility to CQ-bound copper ions. Further studies revealed that CQ sequestrates copper and iron at the cellular membrane, likely the plasma membrane, resulting overall metal accumulation but cytosolic metal depletion. CQ's effects on metal-sensitive metalloenzymes were also verified in mammalian cell line SH-SY5Y. Together, our results revealed that CQ can regulate metal homeostasis by binding metal ions, resulting the cell sensing a state of deficiency of bio-available metal ions while simultaneously increasing available metals to SOD1 (via Ccs1) and possibly some other metalloproteins that can access CQ-bound metals. We hope this regulation of metal homeostasis may be helpful in explaining the therapeutic effects of CQ used in disease treatment. Show more

Keywords: Alzheimer's disease, clioquinol, homeostasis metals, yeast

DOI: 10.3233/JAD-2010-100024

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1249-1262, 2010

Authors: Laske, Christoph | Sopova, Kateryna | Gkotsis, Christos | Eschweiler, Gerhard W. | Straten, Guido | Gawaz, Meinrad | Leyhe, Thomas | Stellos, Konstantinos

Article Type: Research Article

Abstract: Plasma levels of amyloid-β (Aβ) peptides are potential biomarkers of early cognitive impairment and of Alzheimer's disease (AD) risk. However, the association of Aβ peptides with the rate of cognitive decline in AD patients is still unclear. In the present study we demonstrate that Aβ1-42 plasma levels show a significant correlation with the rate of cognitive decline and are significantly increased in AD patients with fast cognitive decline (decrease of Mini-Mental Status Examination (MMSE) score ⩾ 5/year; n=12) compared to AD patients with slow cognitive decline (decrease of MMSE score ⩽ 4/year; n=28), independent of baseline MMSE scores, age …and cholinesterase inhibitor intake, but dependent on history of myocardial infarction and history of stroke in a multivariate analysis. These results suggest that Aβ1-42 plasma levels are associated with the rate of cognitive decline in AD patients and may be influenced by atherosclerotic vasculopathies such as stroke and myocardial infarction. Show more

Keywords: Alzheimer's disease, amyloid-β peptide (Aβ), Aβ1-40, Aβ1-42, cognitive decline, dementia

DOI: 10.3233/JAD-2010-100510

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1263-1269, 2010

Authors: de Wilde, Martijn C. | van der Beek, Eline M. | Kiliaan, Amanda J. | Leenders, Inge | Kuipers, Almar A.M. | Kamphuis, Patrick J. | Broersen, Laus M.

Article Type: Research Article

Abstract: The effect of supplementation with the omega 3 polyunsaturated fatty acid (n-3 PUFA) docosahexaenoic acid (DHA) on membrane composition and amyloid-β1-42 (Aβ42 ) secretion was studied in human amyloid-β protein precursor-transfected Chinese Hamster Ovary (CHO) cells. Twenty-four hour incubation with a range of DHA concentrations resulted in a dose-dependent increase in membrane DHA and eicosapentaenoic acid content and a decrease in arachidonic acid content. In addition, DHA supplementation caused a dose-dependent reduction in the secreted Aβ42 levels and resulted in a 4–8 fold decrease in extracellular prostaglandin E2 (PGE2 ) levels. Tocopherol, which was added to DHA …to prevent oxidation, may have contributed to the effect of DHA, since it slightly decreased extracellular Aβ42 and PGE2 levels when given alone. The addition of selective COX-2 inhibitors Celebrex and curcumin to the culture medium resulted in a significant and comparable inhibition of PGE2 release, but did not inhibit Aβ42 secretion, and even significantly increased Aβ42 production in this cell system. Together, the present data show that, whereas both DHA and COX-2 inhibitors may reduce PGE2 production, only DHA in the presence of tocopherol significantly reduced Aβ42 production and concurrently changed membrane lipid composition in CHO cells. It is concluded that in this in vitro setting DHA reduced Aβ42 secretion through membrane-related, but not PGE2 -related mechanisms. Show more

Keywords: Alzheimer's disease, amyloid-β, COX inhibitor, curcumin, DHA, inflammation, membrane, nutrition

DOI: 10.3233/JAD-2010-091255

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1271-1281, 2010