Journal of Alzheimer's Disease - Volume 20, issue 1

Article Type: Obituary

DOI: 10.3233/JAD-2010-1422

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 1-1, 2010

Authors: Butterfield, D. Allan

Article Type: Obituary

DOI: 10.3233/JAD-2010-100246

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 3-4, 2010

Authors: Arshavsky, Yuri I.

Article Type: Review Article

Abstract: Alzheimer's disease is a neurodegenerative disease whose sole initial symptom is memory impairment. However, the mechanisms which make the neurons involved in learning and memory particularly vulnerable to the formation of amyloid plaques and neurofibrillary tangles remain completely unknown. Here, I propose a hypothesis that may resolve this puzzle. A growing body of evidence suggests that memory formation involves epigenetic mechanisms that regulate patterns of gene expression. Therefore, it is conceivable that the process of memory consolidation may include the synthesis of novel proteins that are recognized by the immune system as "non-self" antigens. Normally, neurons involved in formation and …storage of memory are isolated from the organism's immune system by the blood-brain barrier. Since all known genetic and environmental risk factors for Alzheimer's disease can compromise this barrier, I hypothesize that the disease is initiated as an autoimmune reaction against the memory-bearing neurons. This reaction gradually makes these neurons vulnerable to the subsequent formation of amyloid plaques and neurofibrillary tangles. This hypothesis suggests that early therapy of Alzheimer's disease could be devoted to preventing impairments in the blood-brain barrier. Recent evidence that formation of the blood-brain barrier is controlled via the Wnt/β-catenin signaling pathway may suggest potential directions to addressing this problem. Show more

Keywords: Alzheimer's disease, autoimmune reaction, blood-brain barrier, immune privilege, memory

DOI: 10.3233/JAD-2010-1339

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 5-16, 2010

Authors: Frisardi, Vincenza | Solfrizzi, Vincenzo | Capurso, Cristiano | Kehoe, Patrick G | Imbimbo, Bruno P. | Santamato, Andrea | Dellegrazie, Flora | Seripa, Davide | Pilotto, Alberto | Capurso, Antonio | Panza, Francesco

Article Type: Review Article

Abstract: In recent years, interest in the potential role of metals in the pathogenesis of Alzheimer's disease (AD) has grown considerably. In particular, aluminum (Al) neurotoxicity was suggested after its discovery in the senile plaques and neurofibrillary tangles that represent the principal neuropathological hallmarks of AD. Al is omnipresent in everyday life and can enter the human body from several sources, most notably from drinking water and food consumption. The evidence supporting association from ingestion of Al from drinking water is somewhat stronger than for its ingestion from food. However, other elements present in drinking water, such as fluoride, copper, zinc, …or iron could also have an effect on cognitive impairment or modify any Al neurotoxicity. Some epidemiological studies, but not all, suggested that silica could be protective against Al damage, because it reduces oral absorption of Al and/or enhances Al excretion. Some epidemiological investigations suggested an association between chronic exposure to Al and risk of AD, although this relationship falls short of all the criteria generally attributed to causation. Future studies need to be more rigorous to truly test the validity of previous findings and in doing so attempt to identify dose-response relationships between Al and AD risk which may provide new routes to disease-modifying treatment of AD or possibly some lifestyle modification, to supplement existing symptomatic approaches. Show more

Keywords: Age-related cognitive decline, aluminum, Alzheimer's disease, drinking water assessment, food consumption assessment, mild cognitive impairment

DOI: 10.3233/JAD-2010-1340

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 17-30, 2010

Authors: Mitchell, Jacqueline C. | Perkinton, Michael S. | Yates, Darran M. | Lau, Kwok-Fai | Rogelj, Boris | Miller, Christopher C.J. | McLoughlin, Declan M.

Article Type: Short Communication

Abstract: X11α is a neuronal-specific adaptor protein that binds to the amyloid-β protein precursor (AβPP). Overexpression of X11α reduces Aβ production but whether X11α also protects against Aβ-related memory dysfunction is not known. To test this possibility, we crossed X11α transgenic mice with AβPP-Tg2576 mice. AβPP-Tg2576 mice produce high levels of brain Aβ and develop age-related defects in memory function that correlate with increasing Aβ load. Overexpression of X11α alone had no detectable adverse effect upon behavior. However, X11α reduced brain Aβ levels and corrected spatial reference memory defects in aged X11α/AβPP double transgenics. Thus, X11α may be a therapeutic target …for Alzheimer's disease. Show more

Keywords: Amyloid-β protein precursor, axonal transport, Mint1, protein trafficking, X11α

DOI: 10.3233/JAD-2010-1341

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 31-36, 2010

Authors: Nacmias, Benedetta | Tedde, Andrea | Bagnoli, Silvia | Lucenteforte, Ersilia | Cellini, Elena | Piaceri, Irene | Guarnieri, Bianca Maria | Bessi, Valentina | Bracco, Laura | Sorbi, Sandro

Article Type: Short Communication

Abstract: A recent study identified a polymorphism (Pro86Leu) in the Calcium homeostasis modulator 1 (CALHM1) gene whose minor Leucine allele showed a higher frequency in Alzheimer's disease (AD) patients compared to controls (29% in AD and 22% in controls). Further studies provided conflicting results in different ethnic groups. In order to assess the involvement of the CALHM1 genetic variant on the risk of developing AD, we analyzed the genotype and allele distributions of the Pro86Leu polymorphism in 758 Italian subjects. Our results did not confirm an association between the CALHM1 variation and AD, thus suggesting a genetic heterogeneity among the various …populations. Show more

Keywords: Alzheimer's disease, apolipoprotein E, calcium homeostasis modulator 1, genetic variation

DOI: 10.3233/JAD-2010-1345

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 37-41, 2010

Authors: Piscopo, Paola | Talarico, Giuseppina | Crestini, Alessio | Gasparini, Marina | Malvezzi-Campeggi, Lorenzo | Piacentini, Elisa | Lenzi, Gian Luigi | Bruno, Giuseppe | Confaloni, Annamaria

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) is characterized by accumulation of toxic amyloid-β (Aβ) in the brain, with neuronal death, and an associated increased Aβ42/40 ratio. Several mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid-β precursor protein are involved in the etiology of familial AD (FAD); these mutations alter the Aβ42/40 ratio and promote apoptosis. We describe an Italian pedigree linked to a novel mutation (S175C) at the third transmembrane domain of PSEN2. Clinical phenotype in these individuals is characterized by fast cognitive decline with progressive memory impairment, early involvement of executive functions, behavioral disturbances, and extrapyramidal signs.

Keywords: Atypical dementia, behavioral disturbances, genetics, mutation, presenilins

DOI: 10.3233/JAD-2010-1369

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 43-47, 2010

Authors: Fodero-Tavoletti, Michelle T. | Villemagne, Victor L. | Paterson, Brett M. | White, Anthony R. | Li, Qiao-Xin | Camakaris, James | O'Keefe, Graeme | Cappai, Roberto | Barnham, Kevin J. | Donnelly, Paul S.

Article Type: Research Article

Abstract: A bis (thiosemicarbazonato) complex radiolabeled with positron emitting Cu-64 can be used for a new and alternative method for the non-invasive diagnosis of Alzheimer's disease using positron emission tomography (PET). Most imaging agents being investigated for the diagnosis of Alzheimer's disease target plaque burden but our new approach highlights altered copper homeostasis. This approach has the potential to offer complementary information to other diagnostic procedures that elucidate plaque burden.

Keywords: Alzheimer's disease, copper homeostasis, copper radiopharmaceuticals, diagnostic imaging, positron emission tomography (PET)

DOI: 10.3233/JAD-2010-1359

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 49-55, 2010

Authors: Nair, Nanditha G. | Perry, George | Smith, Mark A. | Reddy, V. Prakash

Article Type: Research Article

Abstract: Amyloid-β (Aβ), the major component of senile plaques in Alzheimer's disease, is known to complex transition metal ions mainly through histidine residues. In this study, using 1 H NMR titration experiments, we show that histidine binds strongly to Zn(II), Cu(II), and Fe(III) ions at a biologically relevant pH (pH 7.4), with a stoichiometry of Zn(II): histidine binding of 1:2. The observed deshielding of the chemical shifts and relative line broadening indicate that Fenton-active Cu(II) and Fe(III) bind to histidine relatively more efficiently as compared to Zn(II). Parallel studies showed that glutamic acid and aspartic acid are relatively inefficient in metal …ion binding. From these studies, we suggest that Aβ-chelated Zn(II) is readily displaced by Cu(II) and Fe(III) ions and leads to a propagation of oxidative stress. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, aspartic acid, Fenton reaction, histidine, glutamic acid, metal ion chelation, NMR titrations, oxidative stress, tyrosine

DOI: 10.3233/JAD-2010-1346

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 57-66, 2010

Authors: Di Paola, Margherita | Spalletta, Gianfranco | Caltagirone, Carlo

Article Type: Research Article

Abstract: The corpus callosum (CC), which connects the two cerebral hemispheres, is the largest white matter fiber bundle in the human brain. This structure presents a peculiar myelination pattern: it has small diameter fibers, located in the genu, which myelinate much later in normal development, and large diameter fibers of the splenium, which myelinate early in development. Although the pathology of AD mainly involves the cerebral gray matter structure, there is evidence that white matter may also be involved. To illustrate callosal white matter changes in AD pathology, in this review we summarize in vivo imaging studies in humans, focusing on …region of interest, voxel-based morphometry, diffusion-weighted imaging, and diffusion tensor imaging techniques. Our aims were to identify where in the CC, when in the different stages of AD, and how callosal changes can be detected with different MRI techniques. Results showed that changes in the anterior (genu and anterior body) as well as in the posterior (isthmus and splenum) portions of the CC might already be present in the early stages of AD. These findings support the hypothesis that two mechanisms, Wallerian degeneration and myelin breakdown, might be responsible for the region-specific changes detected in AD patients. Wallerian degeneration affects the posterior CC subregion, which receives axons directly from those brain areas (temporo-parietal lobe regions) primarily affected by the AD pathology. Instead, the myelin breakdown process affects the later-myelinating CC subregion and explains the earlier involvement of the genu in CC atrophy. Show more

Keywords: Alzheimer's disease, corpus callosum, diffuse tensor imaging, diffusion-weighted imaging, mild cognitive impairment, region of interest, voxel-based morphometry

DOI: 10.3233/JAD-2010-1370

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 67-95, 2010