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  JOURNAL OF ALZHEIMER'S DISEASE

an IOS Press publication

CONTENTS/ABSTRACTS

 PDFs of all articles are available from IOS Press. 

F O R   A U T H O R S

VOLUMES 1-18

VOLUME 19

VOLUME 20

VOLUME 21

VOLUME 22

VOLUME 23

VOLUME 24

VOLUME 25

VOLUME 26

VOLUME 27

VOLUME 28

VOLUME 29

VOLUME 30

VOLUME 31

VOLUME 32

VOLUME 33

VOLUME 34

VOLUME 35

VOLUME 36

The Journal of Alzheimer's Disease is published by IOS Press. 1998-2012 Journal of Alzheimer's Disease

JAD - Volume 16, Number 1

Volume 16, Number 1, January 2009

Pages 1-14
Review

Pontus Wasling, Jonny Daborg, Ilse Riebe, My Andersson, Erik Portelius, Kaj Blennow, Eric Hanse, Henrik Zetterberg
Synaptic Retrogenesis and Amyloid-β in Alzheimer’s Disease
Abstract: Pathological hallmarks of Alzheimer’s disease (AD) include synaptic and neuronal degeneration and the presence of extracellular deposits of amyloid-β (Aβ) in senile plaques in the cerebral cortex. Although these brain lesions may be seen also in aged non-demented individuals, the increase in brain Aβ is believed by many to represent the earliest event in the disease process. Accumulating evidence suggests that Aβ, which is highly conserved by evolution, may have an important physiological role in synapse elimination during brain development. An intriguing idea is that this putative function can become pathogenic if activated in the aging brain. Here, we review the literature on the possible physiological roles of Aβ and its precursor protein AβPP during development with special focus on electrophysiological findings.

Pages 15-27
Review

Han-chang Huang, Zhao-feng Jiang
Accumulated Amyloid-β Peptide and Hyperphosphorylated Tau Protein: Relationship and Links in Alzheimer’s Disease
Abstract: The neuropathology associated with Alzheimer’s disease (AD) is characterized by the presence of extracellularly neuritic plaques, intracellularly neurofibrillary tangles and the loss of basal forebrain cholinergic neurons. The neuritic plaque is composed of a core of amyloid-β peptide (Aβ) while the neurofibrillary tangles contain phosphorylated tau protein, and, as such, both Aβ and tau are important molecules associated with AD. In healthy human bodies, clearance mechanisms for Aβ are available; yet if clearance fails, Aβ accumulates, increasing the risk of neurotoxicity in the brain. Tau, one of the main microtubule-associated proteins, will be hyperphosphorylated and lose the ability to bind microtubules when the homeostasis of phosphorylation and dephosphorylation is disturbed in neurons. Accumulated Aβ and hyperphosphorylated tau are thought to be coexistent. Research on the pathological changes in AD indicates that accumulated Aβ in vivo may initiate the hyperphosphorylation of tau. Also, the signal transduction pathways of tau hyperphosphorylation may be related to accumulated Aβ. In this review, we will discuss how Aβ accumulates, how tau protein is hyperphosphorylated, and how accumulated Aβ initiates hyperphosphorylation of tau protein in AD.

Pages 29-34
Short Communication

Peter T. Nelson, Richard J. Kryscio, Erin A. Abner, Frederick A. Schmitt, Gregory A. Jicha, Marta S. Mendiondo, Greg Cooper, Charles B. Smith, William R Markesbery (Communicated by Thomas Montine)
Acetylcholinesterase Inhibitor Treatment is Associated with Relatively Slow Cognitive Decline in Patients with Alzheimer’s Disease and AD+DLB
Abstract: Dementia can be caused by different diseases including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), or both (AD+DLB). University of Kentucky AD Center pathologically-diagnosed AD and AD+DLB cases were evaluated who had three or more longitudinal antemortem mental status examinations (n=156). Patients with important concomitant pathology (n=5) or patients that were profoundly demented at recruitment (intake MMSE<20; n=86) were excluded to strengthen our ability to test the association of specific clinical and pathological indices. Patients with pathologically-diagnosed AD+DLB (n=25) lost cognitive capacity faster than patients with AD alone (n=40). In both diseases, treatment with acetylcholinesterase inhibitors was associated with a slower rate of cognitive decline.

Pages 35-38
Short Communication

Ignat Ignatov, Christine Belden, Sandra Jacobson, Donald Connor, Marwan N. Sabbagh
Possible Alzheimer’s Disease in an Apolipoprotein E2 Homozygote
Abstract: The objective of this study was to describe a case of Alzheimer’s disease in an ApoE ε2/ε2 homozygote. ApoE ε2/ε2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE ε2/ε2 female who meets clinical criteria for Alzheimer’s disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer’s disease with decline on the Mini-Mental Status Examination from a score of 25 to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer’s disease is rare in Apo E2 homozygotes but can occur.

Pages 39-47
Jia-yu Zhang, Caixia Peng, Hairong Shi, Shaohui Wang, Qun Wang, Jian-Zhi Wang (Communicated by Chengxin Gong)
Inhibition of Autophagy Causes Tau Proteolysis by Activating Calpain in Rat Brain
Abstract: The autophagic lysosomal system contributes to the removal of cytosolic components, and abnormality of lysosomal proteases has been reported in the brain of patients with Alzheimer’s disease (AD). However, the role of lysosome in tau degradation is still elusive. Here, we infused chloroquine, 3-methyladenine or rapamycin into rat hippocampus or the lateral ventricle to manipulate the autophagic activity and measured the levels of tau protein by Western blotting. We unexpectedly observed that the level of different tau species decreased upon inhibition of lysosomal proteases or macroautophagy by chloroquine or 3-methyladenine. Furthermore, induction of autophagic activity by rapamycin did not induce degradation of tau proteins. To explore the underlying mechanisms for the increased tau degradation induced by autophagic inhibition, we used MG-132, an inhibitor of proteasome and calpain. We found that simultaneous inhibition of proteasome and calpain by MG-132 prevented the chloroquine-induced tau degradation. Further studies demonstrated that the activity of calpain was elevated whereas the activity of proteasome was suppressed in response to inhibition of autophagy by 3-methyladenine or chloroquine. Our data suggest that the lysosomal autophagic system may not degrade tau in the normal adult rat brain and inhibition of autophagy may induce tau proteolysis through activating calpain.

Pages 49-57
Wei Zhao, Jun Wang, Lap Ho, Kenjiro Ono, David B. Teplow, Giulio M. Pasinetti
Identification of Antihypertensive Drugs Which Inhibit Amyloid-β Protein Oligomerization
Abstract: Recent studies suggest that certain cardiovascular antihypertensive agents decrease the incidence of Alzheimer’s disease. Based on this evidence and the fact that Aβ aggregation into high-molecular-weight-soluble oligomeric Aβ species is known to directly induce cognitive impairment, we tested the possibility that certain antihypertensive compounds may affect the progression of Alzheimer’s disease, at least in part by influencing the formation of Aβ oligomers. High throughput screening of 55 commercially available antihypertensive drugs identified four compounds that significantly reduced Aβ1-42 oligomerization in a dose dependent manner. These four compounds, furosemide (diuretic), nitrendipine (calcium channel blocker), candesartan cilextil (angiotensin II receptor antagonist) and diazoxide (vasodilator) showed no detectable Aβ lowering activities in primary neuron cultures generated from Tg2576 mouse embryos. However, furosemide, nitrendipine and candesartan cilextil prevented oligomerization of both Aβ1-40 and Aβ1-42 in vitro. Furosemide also dissociated pre-aggregated Aβ1-42 oligomers. Furthermore, short term furosemide treatment resulted in decreased amount of Aβ oligomers in the brain of Tg2576 mice. Our studies suggest that certain antihypertensive compounds may prevent AD-type neuropathology through inhibition of Aβ oligomer formation.

Pages 59-72
Lap Ho, Ling Hong Chen, Jun Wang, Wei Zhao, Stephen T. Talcott, Kenjiro Ono, David Teplow, Nelson Humala, Alice Cheng, Susan S. Percival, Mario Ferruzzi, Elsa Janle, Dara L. Dickstein, Giulio Maria Pasinetti
Heterogeneity in Red Wine Polyphenolic Contents Differentially Influences Alzheimer’s Disease-type Neuropathology and Cognitive Deterioration
Abstract: We recently found that moderate consumption of two un-related red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer’s disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-β (Aβ) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Aβ neuropathology and Aβ-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Aβ molecules to soluble high-molecular-weight Aβ oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Aβ-related mechanisms. Results from these studies suggest the possibility of developing a “combination” of dietary polyphenolic compounds for AD prevention and/or therapy by modulating multiple Aβ-related mechanisms.

Pages 73-84
Monika Ray, Weixiong Zhang
Integrating Gene Expression and Phenotypic Information to Analyze Alzheimer’s Disease
Abstract: The assessment of the relationship between gene expression profiling, clinical and histopathological phenotypes would be better suited to understanding Alzheimer’s disease (AD) pathogenesis. We developed a multiple linear regression (MLR) method to simultaneously model three variables – Mini-Mental Status Examination score, neurofibrillary tangles score and gene expression profile - to identify significant genes. These genes were also used to distinguish subjects with incipient AD from healthy controls. Finally we investigated the behavior of the significant genes across the entorhinal cortex and hippocampus of AD subjects in two different Braak stages. Results indicate that integrating multiple phenotypic and gene expression information of samples increases the power of methods while analyzing small datasets. The MLR method could identify significant genes at reasonable false discovery rates (FDRs), thereby providing a choice of reasonable FDRs. The accuracy in discriminating between subjects affected and unaffected by AD using MLR identified genes was high. We found that transcription and tumor suppressor responses do begin quite early in AD and therefore should be the target of drugs. Several genes were consistently up/down-regulated across the two brain regions and Braak stages and, therefore, can be used as predictive markers to detect AD at an earlier stage.

Pages 85-91
Marjo H. Eskelinen, Tiia Ngandu, Jaakko Tuomilehto, Hilkka Soininen, Miia Kivipelto
Midlife Coffee and Tea Drinking and the Risk of Late-Life Dementia: A Population-Based CAIDE Study
Abstract: Caffeine stimulates central nervous system on a short term. However, the long-term impact of caffeine on cognition remains unclear. We aimed to study the association between coffee and/or tea consumption at midlife and dementia/Alzheimer's disease (AD) risk in late-life. Participants of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were randomly selected from the survivors of a population-based cohorts previously surveyed within the North Karelia Project and the FINMONICA study in 1972, 1977, 1982 or 1987 (midlife visit). After an average follow-up of 21 years, 1409 individuals (71%) aged 65 to 79 completed the re-examination in 1998. A total of 61 cases were identified as demented (48 with AD). Coffee drinkers at midlife had lower risk of dementia and AD later in life compared with those drinking no or only little coffee adjusted for demographic, lifestyle and vascular factors, apolipoprotein E ε4 allele and depressive symptoms. The lowest risk (65% decreased) was found in people who drank 3-5 cups per day. Tea drinking was relatively uncommon and was not associated with dementia/AD. Coffee drinking at midlife is associated with a decreased risk of dementia/AD later in life. This finding might open possibilities for prevention of dementia/AD.

Pages 93-98
Gene L. Bowman, Hiroko Dodge, Carlo Calabrese, Barry S. Oken, Balz Frei, Jeffrey A. Kaye, Joseph F. Quinn
Ascorbic Acid and Rates of Cognitive Decline in Alzheimer’s Disease
Abstract: The brain maintains high levels of ascorbic acid (AA) despite a concentration gradient favoring diffusion from brain to plasma. Dietary antioxidants, including AA, appear to modify the risk of Alzheimer’s disease (AD). The objective of this study was to test the hypothesis that neurodegeneration in AD is modified by brain levels of AA. Thirty-two patients with mild to moderate AD participated in a biomarker study involving standardized clinical assessments over one year. Cerebrospinal fluid (CSF) and serum were collected at baseline for AA and albumin content. Cognitive measures were collected at baseline and one year. CSF and plasma AA failed to predict cognitive decline independently, however, CSF: plasma AA ratio did. After adding CSF Albumin Index (an established marker of blood-brain barrier integrity) to the regression models the effect of CSF: plasma AA ratio as a predictor of cognitive decline was weakened significantly on two of the three cognitive outcomes. CSF: plasma AA ratio predicts rate of decline in AD. This relationship may indicate that the CSF: plasma AA ratio is an index of AA availability to the brain or may be an artifact of a relationship between blood-brain barrier impairment and neurodegeneration.

Pages 99-111
Sangmook Lee, Cheolwha Jung, Gloria Lee, Garth F. Hall (Communicated by Jesus Avila)
Exonic Point Mutations of Human Tau Enhance its Toxicity and Cause Characteristic Changes in Neuronal Morphology, Tau Distribution and Tau Phosphorylation in the Lamprey Cellular Model of Tauopathy
Abstract: Exonic mutations in the gene coding for human tau cause familial neurofibrillary degenerative diseases (tauopathies) which exhibit mutation-specific characteristics. It is thus unclear whether such mutations have similar effects on tau structure and function in vivo and if they act via similar cytopathological mechanisms in vulnerable neuron types. We have previously shown that overexpressing wild type human tau isoforms in identified giant neurons (ABCs) of the lamprey CNS results in characteristic, stereotyped cytopathological changes in these cells over several weeks. Here, we use this model to compare the cytopathological consequences of expressing wild type and exonic mutant tau isoforms (P301L, G272V, V337M, and R406W) at a high level of resolution. We show that each of the four exonic htau mutations tested accelerate degeneration in ABCs when compared to their WT parent isoforms, and that the patterns of human tau distribution, phosphorylation and cytopathology, while similar, vary characteristically from one another among both WT and mutant isoforms in a single identified neuron in situ. Our results therefore suggest that at least some of the differences between the effects of these mutations in humans are due to cell autonomous, mutation specific differences in the cytopathological mechanism of tau-induced neurodegeneration.

Pages 113-120
Massimo Leandri, Sharon Cammisuli, Sergio Cammarata, Luigi Baratto, Jackie Campbell, Marina Simonini, Massimo Tabaton
Balance features in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment
Abstract: We evaluated alterations of balance by stabilometry in patients with amnestic mild cognitive impairment (aMCI) and with mild-moderate Alzheimer’s disease (AD). Fifteen patients with aMCI and 15 with mild AD were recruited according to the current diagnostic criteria. Fifteen healthy subjects of the same age range were recruited as controls. Stabilometry was carried out using a commercial 4 load cell platform. Statistical analysis of between group differences was performed using one-way analysis of variance for parametric data and Kruskal-Wallis tests for non-parametric data. Spearman correlation coefficients were used to investigate the association between cognitive test scores and stabilometric data. All stabilometry measures were significantly altered in mild AD patients compared to normal controls. Antero-posterior sway was found to be the most sensitive parameter, since it correlated with the ADAS-cog orientation subscale in AD patients, and also discriminated between aMCI and normal controls. Our study shows that impairment in balance is a feature not only of AD, but also of aMCI. The alterations found suggest that a progressive failure of the vestibular system, possibly linked to reduced hippocampal performance, may be responsible for such a feature. Further research must be focused on studying the predictive value of stabilometry in the conversion of aMCI.

Pages 121-131
Woojin Scott Kim, Sharon L. Chan, Andrew F. Hill, Gilles J. Guillemin, Brett Garner
Impact of 27-Hydroxycholesterol on Amyloid-β Peptide Production and ATP-Binding Cassette Transporter Expression in Primary Human Neurons
Abstract: Cholesterol is an integral component of neuronal membranes and recent evidence has shown that it regulates amyloid-β protein precursor processing to form amyloid-β peptides, which are a major constituent of cerebral amyloid plaques associated with Alzheimer’s disease. 27-Hydroxycholesterol (27OHC) is synthesized from cholesterol via sterol 27-hydroxylase (CYP27A1) in the brain and, unlike cholesterol, can cross into the brain through the blood brain barrier from the circulation. Previous studies point toward a potential role for 27OHC in the regulation of neuronal amyloid-β peptide generation, however, this has not been investigated in primary human neurons. Here we show that 27OHC significantly reduced amyloid-β peptide detected in cell culture supernatants from primary human neurons. We also show that 27OHC does not affect α-, β- or γ-secretase activity but does upregulate the liver X receptor (LXR) responsive genes ABCA1, ABCG1 and APOE. These data suggest that 27OHC-mediated reduction in extracellular amyloid-β peptide levels is potentially due to its action as an LXR ligand.

Supplementary Data for Kim et al. article

Pages 133-147
Morgan Newman, Ben Tucker, Svanhild Nornes, Alistar Ward, Michael Lardelli
Altering Presenilin Gene Activity in Zebrafish Embryos Causes Changes in Expression of Genes with Potential Involvement in Alzheimer’s Disease Pathogenesis
Abstract: Aberrant splicing and point mutations in the human presenilin genes, PSEN1 and PSEN2, have been linked to familial forms of Alzheimer’s disease. We have previously described that low-level aberrant splicing of exon 8 in zebrafish psen1 transcripts in zebrafish embryos produces potent dominant negative effects that increase psen1 transcription, cause a dramatic hydrocephalus phenotype, decreased pigmentation and other developmental defects. Similar effects are also observed after low-level interference with splicing of exon 8 of psen2. To determine the molecular etiology of these effects, we performed microarray analyses of global gene expression changes. Of the 100 genes that showed greatest dysregulation after either psen1 or psen2 manipulation, 12 genes were common to both treatments. Five of these have known function and showed increased expression: cyclin G1 (ccng1), prosaposin (psap), cathepsin Lb (ctslb), heat shock protein 70kDa (hsp70) and hatching enzyme 1 (he1). We used phylogenetic and conserved synteny analysis to confirm the orthology of zebrafish ccng1 with human CCNG1. We analyzed the expression of zebrafish ccng1 in developing embryos to 24 hours post fertilization (hpf). Decreased ccng1 expression does not rescue the hydrocephalus or pigmentation phenotypes of embryos with aberrant splicing of psen1 exon 8.

Pages 149-156
Paula Hernandez, Gloria Lee, Marcela Sjoberg, Ricardo B. Maccioni
Tau Phosphorylation by cdk5 and Fyn in Response to Amyloid Peptide A25‑35: Involvement of Lipid Rafts
Abstract: Alzheimer’s disease (AD) is characterized by accumulation of protein filaments, namely extracellular amyloid-β (Aβ) fibrils and intracellular neurofibrillary tangles, which are composed of aggregated hyperphosphorylated tau. Tau hyperphosphorylation is the product of deregulated Ser/Thr kinases such as cdk5 and GSK3β. In addition, tau hyperphosphorylation also occurs at Tyr residues. To find a link between Aβ and tau phosphorylation, we investigated the effects of short-term Aβ treatments on SHSY-5Y cells. We analyzed phosphorylated tau variants in lipid rafts and the possible role of Tyr18 and Ser396/404 tau phosphorylation in Aβ-induced signaling cascades. After 2 min of Aβ treatment, phospho-Tyr18-tau and its association with rafts increased. Phospho-Ser 396/404-tau became detectable in rafts after 10 min treatment, which temporally correlated with the detection of cdk5 and p35 activator in lipid rafts. To determine the role of cdk5 in tau phosphorylation at Ser396/404 in lipid rafts, we pre‑incubated cells with cdk5 inhibitor roscovitine, and observed that the Aβ-induced tau phosphorylation at Ser 396/404 in rafts was abolished as well as cdk5/p35 association with rafts. These data suggest a role for cdk5 in the Aβ‑promoted early events involving tau hyperphosphorylation, and their possible implications for AD pathogenesis.

Pages 157-165
Helmut Hildebrandt, Andreas Haldenwanger, Paul Eling
False Recognition Correlates with Amyloid-β1-42 but not with Total Tau in Cerebrospinal Fluid of Patients with Dementia and Mild Cognitive Impairment
Abstract: Severe memory impairment forms the core symptom of Alzheimer’s disease (AD), which is present early in the disease course. Recent studies show that AD patients not only suffer from forgetfulness, but also differ in their response bias, when having to decide whether information has been perceived recently, or whether it is only familiar or semantically related to perceived information. Changes in total tau-protein and amyloid-β (Aβ)1-42 concentration in cerebrospinal fluid are also features of AD, and they predict conversion from mild cognitive impairment to dementia. In this study we correlated recognition scores with total tau and Aβ1-42 concentrations in patients with suggested dementia. We studied 40 patients and 21 healthy controls, using an incidental recognition memory task and a neuropsychological test battery. False recognition scores correlated with delayed recall and with Aβ1-42, and Aβ1-42 tended to correlate with delayed recall. Total tau, however, did not correlate with memory scores or with neuropsychological performance in general. We suggest that Aβ1-42 may indicate a reduction in the specificity of the neuronal response in the limbic cortex, due to agglomeration of plaques. This process might be more specific for AD than the increase of tau, and therefore it is stronger correlated with recognition errors.

Pages 167-171
Amy Chan and Thomas B. Shea
Dietary Supplementation with Apple Juice Decreases Endogenous Amyloid-β Levels in Murine Brain
Abstract: Folate deficiency has been associated with age-related neurodegeneration. We demonstrate herein that dietary deficiency in folate and vitamin E, coupled pro-oxidant stress induced by dietary iron, increased amyloid-β (Aβ) levels in normal adult mice. This increase was potentiated by apolipoprotein E (ApoE) deficiency as shown by treatment of transgenic mice homozygously lacking murine ApoE. Dietary supplementation with apple juice concentrate in drinking water alleviated the increase in Aβ for both mouse genotypes. These findings provide further evidence linking nutritional and genetic risk factors for age-related neurodegeneration, and underscore that dietary supplementation may be useful to augment therapeutic approaches.

Pages 173-180
Davide Quaranta, Alessandra Bizzarro, Camillo Marra, Maria Gabriella Vita, Davide Seripa, Alberto Pilotto, Valeria Sebastiani, Patrizia Mecocci, Carlo Masullo
Psychotic Symptoms in Alzheimer’s Disease and 5-HTTLPR Polymorphism of the Serotonin Transporter Gene: Evidence for an Association
Abstract: The occurrence of psychotic symptoms is common in Alzheimer’s disease (AD), configuring a possibly distinguished clinical entity defined “Psychosis in Alzheimer’s Disease” (AD-P). In order to investigate demographic clinical and biological variables potentially associated to the occurrence of AD-P, 148 AD patients were selected. Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) scores, socio-economic status and 5-HTTLPR and APOE gene polymorphisms were determined for each subject. AD-P patients were significantly more frequent carriers of the long (L) allele of 5-HTTLPR. The percentage of AD-P increased with the number of copies of the L-allele: 13% among S homozygote; 36% among heterozygotes; 51% among L-homozygotes. No difference resulted between AD-P and non-psychotic AD (AD-NP) in the distribution of the ε4 allele of APOE. The risk of AD-P was increased in L/L homozygous (OR=7.25, p=0.003) and, to a lesser extent, in heterozygous (OR=3.91; p= 0.018). Backward logistic regression analysis showed that the risk for AD-P was increased in older subjects (OR=1.07; p=0.018) while an increase of MMSE score was protective (OR=0.90; p=0.004). The occurrence of AD-P resulted significantly related to age at examination, cognitive status, and to the presence of the 5-HTTLPR L-allele.

Pages 181-187
Alessandro Serretti, Paolo Olgiati, Antonis Politis, Petros Malitas, Diego Albani, Sabrina Dusi, Letizia Polito, Stefania De Mauro, Aikaterini Zisaki, Christina Piperi, Ioannis Liappas, Evangelia Stamouli, Antonis Mailis, Anna Rita Atti, Monica Morri, Manjola Ujkaj, Sara Batelli, Gianluigi Forloni, Costantine R. Soldatos, George N. Papadimitriou, Diana De Ronchi, Anastasios Kalofoutis
Lack of Association between Interleukin-1 alpha rs1800587 Polymorphism and Alzheimer’s Disease in Two Independent European Samples
Abstract: Interleukin-1 (IL1) can contribute to pathophysiology of Alzheimer’s disease (AD) by promoting deposition of amyloid-β in the brain. The gene encoding IL1 alpha (IL1A) has a common polymorphism in its 5' regulatory region (rs1800587) with possible functional effects. IL1A T/T genotype has been associated with AD but the overall effect is modest and negative studies have been published. The aim of this study was to investigate the association of the IL1A rs1800587 polymorphism with AD in two independent case-control groups from Greece (Athens) and Italy (Bologna). Preliminary results from the ongoing sample (110 patients with sporadic AD and 130 nonpsychiatric controls) showed no association between IL1A variants and AD, however C/T heterozygotes had more severe depression in AD (Cornell Scale for Depression in Dementia) compared to other genotypes (F=4.56, d.f=1, p=0.037) after controlling for age, illness duration and cognitive impairment (MMSE). Despite the small sample size and the possibility of a false negative finding, our preliminary data support the hypothesis the IL1A rs1800587 variants are not associated with AD. The effect of the IL1A on depressive symptomatology warrants further investigations, however the lack of a gene-dose relationship would suggest a false positive.

Pages 189-196
Gábor Juhász, Árpád Márki, Gabriella Vass, Lívia Fülöp, Dénes Budai, Botond Penke, György Falkay, Viktor Szegedi (Communicated by Ved Chauhan)
An Intraperitoneally Administered Pentapeptide Protects Against Aβ1-42 Induced Neuronal Excitation In Vivo
Abstract: The underlying cause of Alzheimer’s disease (AD) is thought to be the accumulation and aggregation of a misfolded protein, amyloid-β (Aβ). A promising strategy against AD is the application of protective, peptide-based neuroprotective agents that selectively bind to Aβ. We recently described a pentapeptide, LPYFDa, which recognizes Aβ1-42 and protects neurons against the toxic effects of aggregated Aβ1-42 both in vitro and in vivo. Our previous work indicated that the in vivo ejection of fibrillar Aβ1-42 into the hippocampal CA1 region resulted in a massive increase in the NMDA-evoked neuronal firing rate. Our current aim was to study whether intraperitoneally administered LPYFDa is capable of protecting against the synaptotoxic action of fibrillar Aβ1-42 administered by iontophoresis. Our investigations of the in vivo biodistribution of tritium-labelled LPYFDa and single-unit electrophysiology revealed that LPYFDa readily crosses the blood-brain barrier, and protects the synapses against the excitatory action of fibrillar Aβ1-42 in a relatively wide temporal window in rat. This pentapeptide may serve as a lead compound for the design of novel drug candidates for the prevention of AD.

Pages 197-205
Transcript of Live Discussion held at the Alzheimer Research Forum
Mice on Trial? Issues in the Design of Drug Studies

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