Journal of Alzheimer's Disease - Volume 20, issue 4

Authors: Laumet, Geoffroy | Chouraki, Vincent | Grenier-Boley, Benjamin | Legry, Vanessa | Heath, Simon | Zelenika, Diana | Fievet, Nathalie | Hannequin, Didier | Delepine, Marc | Pasquier, Florence | Hanon, Olivier | Brice, Alexis | Epelbaum, Jacques | Berr, Claudine | Dartigues, Jean-Francois | Tzourio, Christophe | Campion, Dominique | Lathrop, Mark | Bertram, Lars | Amouyel, Philippe | Lambert, Jean-Charles

Article Type: Research Article

Abstract: We selected twenty genes from the "Top Results" list on the AlzGene database website and assessed their association with risk of developing Alzheimer's disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, …and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses. Show more

Keywords: AlzGene database, Alzheimer's disease, association, GWAS, replication, risk factor, SNPs

DOI: 10.3233/JAD-2010-100126

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1181-1188, 2010

Authors: Wang, Hong-Mei | Zhao, Yan-Xin | Zhang, Shi | Liu, Gui-Dong | Kang, Wen-Yan | Tang, Hui-Dong | Ding, Jian-Qing | Chen, Sheng-Di

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-β (Aβ) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence …of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-β protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor γ (PPARγ) was decreased in Aβ25-35 -treated astrocytes. In line with these results, nuclear factor-κB translocation was increased in the presence of Aβ. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARγ antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARγ agonist to inhibit the inflammation in Aβ-treated astrocytes. Show more

Keywords: Amyloid-β peptide, astrocyte, curcumin, inflammatory response, nuclear factor-κB, peroxisome proliferator-activated receptor γ

DOI: 10.3233/JAD-2010-091336

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1189-1199, 2010

Authors: Holm, Peter | Ettrup, Anders | Klein, Anders B. | Santini, Martin A. | El-Sayed, Mona | Elvang, Anders B. | Stensbøl, Tine B. | Mikkelsen, Jens D. | Knudsen, Gitte M. | Aznar, Susana

Article Type: Research Article

Abstract: Intrahippocampal injections of aggregated amyloid-β (Aβ)1-42 in rats result in memory impairment and in reduction of hippocampal 5-HT2A receptor levels. In order to investigate how changes in 5-HT2A levels and functionality relate to the progressive accumulation of Aβ protein, we studied 5-HT2A receptor regulation in double transgenic AβPPswe/PS1dE9 mice which display excess production of Aβ and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3 H]-MDL100907, [3 H]-escitalopram, and [11 C]-PIB autoradiography was performed for measuring 5-HT2A receptor, serotonin transporter (SERT), and Aβ plaque levels …in medial prefrontal cortex (mPFC), prefrontal cortex (PFC), frontoparietal cortex (FPC), dorsal and ventral hippocampus, and somatosensory cortex. To investigate 5-HT2A receptor functionality, animals were treated with the 5-HT2A receptor agonist DOI and head-twitch response (HTR) subsequently recorded. Expression level of the immediate early gene c-fos was measured by in situ hybridization. We found that the age-related increase in Aβ plaque burden was accompanied by a significant decrease in 5-HT2A receptor binding in mPFC in the 11-month-old group. The changes in 5-HT2A receptor binding correlated negatively with [11 C]-PIB binding and were not accompanied by decreases in SERT binding. Correspondingly, 11-month-old transgenic mice showed diminished DOI-induced HTR and reduced increase in expression of c-fos mRNA in mPFC and FPC. These observations point towards a direct association between Aβ accumulation and changes in 5-HT2A receptor expression that is independent of upstream changes in the serotonergic system. Show more

Keywords: Alzheimer's disease, amyloid-β, frontoparietal cortex, hippocampus, prefrontal cortex, receptor functionality, serotonin receptor, somatosensory cortex, transgenic mice

DOI: 10.3233/JAD-2010-100117

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1201-1213, 2010

Authors: Kojro, Elzbieta | Füger, Petra | Prinzen, Claudia | Kanarek, Anna Maria | Rat, Dorothea | Endres, Kristina | Fahrenholz, Falk | Postina, Rolf

Article Type: Research Article

Abstract: Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-β protein precursor (AβPP) and are reported to stimulate the activity of α-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the α-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in α-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates α-secretase activity. Treatment of human neuroblastoma cells with 50 μM zaragozic acid resulted in a …∼3 fold increase of α-secretase activity and reduced cellular cholesterol by ∼30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 μM). Zaragozic acid-stimulated secretion of α-secretase-cleaved soluble AβPP was dose dependent and saturable. Lovastatin- or zaragozic acid-stimulated increase of α-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the α-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave AβPP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for α-secretase activation. Show more

Keywords: ADAM10, α-secretase, Alzheimer's disease, lovastatin, shedding, Zaragozic acid A

DOI: 10.3233/JAD-2010-091621

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1215-1231, 2010

Authors: Lui, James K. | Laws, Simon M. | Li, Qiao-Xin | Villemagne, Victor L. | Ames, David | Brown, Belinda | Bush, Ashley I. | De Ruyck, Karl | Dromey, Jasmin | Ellis, Kathryn A. | Faux, Noel G. | Foster, Jonathan | Fowler, Christopher | Gupta, Veer | Hudson, Peter | Laughton, Katrina | Masters, Colin L. | Pertile, Kelly | Rembach, Alan | Rimajova, Mira | Rodrigues, Mark | Rowe, Christopher C. | Rumble, Rebecca | Szoeke, Cassandra | Taddei, Kevin | Taddei, Tania | Trounson, Brett | Ward, Vanessa | Martins, Ralph N. | for the AIBL Research Group

Article Type: Research Article

Abstract: Amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Aβ as an AD biomarker and its relationship with Aβ load and to determine the effect of different assay methods on the interpretation of Aβ levels. Plasma Aβ1-40 , Aβ1-42 , and N-terminal cleaved fragments were measured using both a commercial multiplex assay and a well-documented ELISA in 1032 individuals …drawn from the well-characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Further, Aβ levels were compared to Aβ load derived from positron-emission tomography (PET) with the Pittsburgh compound B (PiB). Lower Aβ1-42 and Aβ1-42/1-40 ratio were observed in patients with AD and inversely correlated with PiB-PET derived Aβ load. However, assay methodology significantly impacted the interpretation of data. The cross-sectional analysis of plasma Aβ isoforms suggests that they may not be sufficient per se to diagnose AD. The value of their measurement in prognosis and monitoring of AD interventions needs further study, in addition to future longitudinal comparisons together with other predictors, which will determine whether plasma Aβ has diagnostic value in a panel of biomarkers. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, diagnosis, Pittsburgh Compound B, positron-emission topography

DOI: 10.3233/JAD-2010-090249

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1233-1242, 2010

Authors: Prakasam, Annamalai | Muthuswamy, Anusuya | Ablonczy, Zsolt | Greig, Nigel H. | Fauq, Abdul | Rao, Kosagisharaf Jagannatha | Pappolla, Miguel A. | Sambamurti, Kumar

Article Type: Research Article

Abstract: Amyloid-β (Aβ) accumulates in several types of retinal degeneration and in Alzheimer’s disease (AD), but its source has been unclear. We detected the neuronal 695 amino acid form of amyloid-β protein precursor (AβPP) in the normal retina and AβPP751 in the retinal pigment epithelium (RPE) and anterior eye tissues. Similar to the brain, a- and β-secretases cleaved AβPP to soluble derivatives (sAβPP) a or β and membrane-bound C-terminal fragments a or β in the retina and RPE. Levels of sAβPP were particularly high in the vitreous and low in aqueous humor revealing a molecular barrier for AβPP. In contrast, Aβ40 …and Aβ42 levels were only 50% lower in the aqueous than the vitreous humor, indicating relatively barrier-free movement of Aβ. These studies demonstrated a relatively high yield of AβPP and Aβ in the ocular fluids, which may serve as a trackable marker for AD. In addition, failure of free clearance from the eye may trigger retina degeneration in a manner similar to Aβ-related neurodegeneration in AD. Show more

Keywords: Age-related macular degeneration, Alzheimer’s disease, amyloid-β protein precursor, aqueous humor, degeneration, eye vitreous humor, glaucoma, retina

DOI: 10.3233/JAD-2010-100210

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1243-1253, 2010

Authors: Strobel, Gabrielle

Article Type: Editorial

DOI: 10.3233/JAD-2010-100213

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1255-1260, 2010

Article Type: Correction

Abstract: Erratum for Journal of Alzheimer's Disease 20(1), 2010, 127–134. http://iospress.metapress.com/content/g232v0t211450061/

DOI: 10.3233/JAD-2010-1425

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1261-1261, 2010

Article Type: Correction

Abstract: Erratum for Journal of Alzheimer's Disease 19(3), 2010, 761–780. http://iospress.metapress.com/content/c07066424h32942g/

DOI: 10.3233/JAD-2010-1426

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1263-1263, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-100211

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1265-1266, 2010