Journal of Alzheimer's Disease - Volume 16, issue 1

Authors: Lee, Sangmook | Jung, Cheolwha | Lee, Gloria | Hall, Garth F.

Article Type: Research Article

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. Show more

Keywords: Exonic mutation, human tau, in situ cellular model, tauopathy

DOI: 10.3233/JAD-2009-0954

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 99-111, 2009

Authors: Leandri, Massimo | Cammisuli, Sharon | Cammarata, Sergio | Baratto, Luigi | Campbell, Jackie | Simonini, Marina | Tabaton, Massimo

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, orientation, postural balance, stabilometry

DOI: 10.3233/JAD-2009-0928

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 113-120, 2009

Authors: Scott Kim, Woojin | Chan, Sharon L. | Hill, Andrew F. | Guillemin, Gilles J. | Garner, Brett

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, ATP-binding cassette transporters, 27-hydroxycholesterol, primary human neurons

DOI: 10.3233/JAD-2009-0944

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 121-131, 2009

Authors: Newman, Morgan | Tucker, Ben | Nornes, Svanhild | Ward, Alister | Lardelli, Michael

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, cyclin G1, presenilin, prosaposin, zebrafish

DOI: 10.3233/JAD-2009-0945

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 133-147, 2009

Authors: Hernandez, Paula | Lee, Gloria | Sjoberg, Marcela | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by the 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. Show more

Keywords: Alzheimer's disease, amyloid-β, cdk5, Fyn, lipid rafts, neuronal membrane, tau phosphorylation

DOI: 10.3233/JAD-2009-0933

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 149-156, 2009

Authors: Hildebrandt, Helmut | Haldenwanger, Andreas | Eling, Paul

Article Type: Research Article

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. Show more

Keywords: Amyloid-β1–42, dementia, false recognition, memory, total tau

DOI: 10.3233/JAD-2009-0931

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 157-165, 2009

Authors: Chan, Amy | Shea, Thomas B.

Article Type: Research Article

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.

Keywords: Alzheimer disease, amyloid-β, apolipoprotein E, apple juice, γ-secretase, nutrition, presenilin

DOI: 10.3233/JAD-2009-0959

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 167-171, 2009

Authors: Quaranta, Davide | Bizzarro, Alessandra | Marra, Camillo | Vita, Maria Gabriella | Seripa, Davide | Pilotto, Alberto | Sebastiani, Valeria | Mecocci, Patrizia | Masullo, Carlo

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, APOE gene polymorphisms, 5-HTT gene, 5-HTTLPR, neuropsychiatric inventory, psychotic symptomatology

DOI: 10.3233/JAD-2009-0950

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 173-180, 2009

Authors: Serretti, Alessandro | Olgiati, Paolo | Politis, Antonis | Malitas, Petros | Albani, Diego | Dusi, Sabrina | Polito, Letizia | De Mauro, Stefania | Zisaki, Aikaterini | Piperi, Christina | Liappas, Ioannis | Stamouli, Evangelia | Mailis, Antonis | Atti, Anna Rita | Morri, Monica | Ujkaj, Manjola | Batelli, Sara | Forloni, Gianluigi | Soldatos, Costantine R. | Papadimitriou, George N. | De Ronchi, Diana | Kalofoutis, Anastasios

Article Type: Research Article

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 (Faenza and Granarolo). 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. Show more

Keywords: Alzheimer's disease, IL-1A gene, inflammatory cytokines, psychosis

DOI: 10.3233/JAD-2009-0946

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 181-187, 2009

Authors: Juhász, Gábor | Márki, Árpád | Vass, Gabriella | Fülöp, Lívia | Budai, Dénes | Penke, Botond | Falkay, György | Szegedi, Viktor

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, hippocampus, neuroprotection, NMDA, protective pentapeptide, single-unit

DOI: 10.3233/JAD-2009-0947

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 189-196, 2009

Article Type: Discussion

DOI: 10.3233/JAD-2009-0961

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 197-205, 2009

Article Type: Announcement

DOI: 10.3233/JAD-2009-1000

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 207-209, 2009