Journal of Alzheimer's Disease - Volume 6, issue 3

Authors: Echeverria, Valentina | Ducatenzeiler, Adriana | Alhonen, Leena | Janne, Juhani | Grant, Susan M. | Wandosell, Francisco | Muro, Andres | Baralle, Francisco | Li, Hongshan | Duff, Karen | Szyf, Moshe | Cuello, A. Claudio

Article Type: Research Article

Abstract: In this communication we report the characterization of several transgenic rat lines expressing human AβPP carrying the Swedish and Indiana mutations (coded UKUR28), the human presenilin 1 transgene with the 'Finn' mutation (coded UKUR19) and double transgenic rats expressing both transgenes (coded UKUR25). In these Tg rats, the AβPP and PS1 transgene expression was largely restricted to the hippocampus and neocortex. The PS1 transgenic rats did not produce visible changes in Aβ immunoreactivity. The AβPP transgenic rats (both the single Tg UKUR28, and double Tg UKUR25) generated a phenotype of intra-neuronalβ accumulation without plaque formation and with no increased immunoreactivity …for AβPP amino and carboxyl-terminal epitopes. This phenotype was apparent as early as 6 months of age in the transgenic rat lines carrying the human AβPP transgene. No senile plaques of aggregated Aβ were observed in any of the transgenic lines generated, up to 24 months of age. The hAβPP single homozygous Tg line (UKUR28) showed an increase in ERK2, without changes in glycogen synthase kinase 3 (GSK3) activity. A preliminary protein analysis of the hippocampus of the double transgenic rat (UKUR25) by mass spectrometry showed differences in the protein profile between this transgenic line and controls. Show more

Keywords: Amyloid-β, transgenic rat, ERK/MAPK, tau phosphorylation

DOI: 10.3233/JAD-2004-6301

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 209-219, 2004

Authors: Burkhardt, M.S. | Foster, J.K. | Laws, S.M. | Baker, L.D. | Craft, S. | Gandy, S.E. | Stuckey, B.G.A. | Clarnette, R. | Nolan, D. | Hewson-Bower, B. | Martins, R.N.

Article Type: Research Article

Abstract: There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an ε4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents …a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 ± 6.34); ERT non-users (n = 80, mean age 67.03 ± 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2–5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE ε4 allele. APOEε4 carriers receiving ERT performed no better on episodic memory testing than APOE ε4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE ε4 allele. Show more

Keywords: oestrogen supplementation, post-menopausal women, cognition, apolipoprotein E genotype, Alzheimer's disease

DOI: 10.3233/JAD-2004-6302

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 221-228, 2004

Authors: Bowen, Richard L. | Gregory, Christopher W.

Article Type: Article Commentary

DOI: 10.3233/JAD-2004-6303

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 229-230, 2004

Authors: de la Monte, Suzanne M. | Wands, Jack R.

Article Type: Research Article

Abstract: Alzheimer-associated neuronal thread protein, AD7c-NTP, accumulates in cortical neurons and co-localizes with phospho-tau-containing cytoskeletal lesions in brains with AD. Over-expression of AD7c-NTP results in increased neuronal death mediated by apoptosis and mitochondrial dysfunction. Empirical studies demonstrating differential growth factor responses to AD7c-NTP led to us to further investigate the effects of insulin, insulin-like growth factor, type 1 (IGF-1), nerve growth factor (NGF), and platelet-derived growth factor (PDGF) stimulation on neuronal survival mechanisms in relation to AD7c-NTP expression. PNET2 human CNS-derived neuronal cells were stably transfected with a cDNA encoding AD7c-NTP or chloramphenicol acetyl transferase (CAT) whereby gene expression was regulated …by an inducible promoter. In cells that expressed AD7c-NTP, insulin or IGF-1 stimulation was associated with reduced viability with increased levels of p53, p21/Waf-1, phospho-JNK, and phospho-tau, and reduced levels of Bcl-2 and phospho-Erk MAPK. In contrast, AD7c-NTP-transfected cells stimulated with NGF or PDGF, and CAT-transfected cells stimulated with any one of the four growth factors remained viable and had low levels of p53, p21/Waf-1, phospho-JNK, and phospho-tau, and abundant Bcl-2 and phospho-Erk expression. The results suggest that reduced survival in neurons that over-express AD7c-NTP may be mediated by impaired insulin/IGF-1 signaling, and that CNS neurons with abundant insulin or IGF-1 receptors may be particularly vulnerable to the adverse effects of AD7c-NTP. Show more

Keywords: neuronal thread protein, apoptosis, neuritic sprouting, growth factors, neuronal cytoskeleton

DOI: 10.3233/JAD-2004-6304

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 231-242, 2004

Authors: Bobich, Joseph A. | Zheng, Qian | Campbell, Arezoo

Article Type: Research Article

Abstract: We wish to understand the normal function of amyloid-β peptides (Aβ) and to see if they destabilize neuronal calcium homeostasis [Mattson et al., J. Neurosci. 12 (1992), 376–389]. We observed that a physiological concentration (10 nM) of Aβ1-42 increased both glutamate and noradrenaline exocytosis from rat cortical nerve endings at least in part by activation of N-type Ca2+ channels. Aβ oligomers rather than monomers or fibrils probably are the most active form. Three alternatively-proposed effects of Aβ (reactive oxygen species formation, membrane perforation, and disruption of Ca2+ stores) also were tested by incubating nerve endings with a …relatively high (by this study's standards) concentration of Aβ1-42 (100 nM). None of the three proposed effects were detected during these incubations. These results support the hypothesis that persistent elevations of Aβ, which normally operates as a modulator of N-type voltage gated calcium channels, could increase internal nerve ending Ca2+ and excitatory neurotransmitter release to produce the early neurotoxic effects that eventually lead to Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid beta peptide, glutamate, neurotransmitter release, excitotoxicity, noradrenaline

DOI: 10.3233/JAD-2004-6305

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 243-255, 2004

Authors: Shiozaki, Aiko | Tsuji, Teruyuki | Kohno, Ryuichi | Kawamata, Jun | Uemura, Kengo | Teraoka, Hiroshi | Shimohama, Shun

Article Type: Research Article

Abstract: Quantitative proteome analysis of Alzheimer's disease (AD) brains was performed using two-dimensional (2-D) gels in order to find out the pathological protein expression in AD. We sequentially extracted brain proteins using two distinct sample solutions, yielding different protein fractions (fraction A and B). These fractions showed distinct 2-DE patterns with high resolution and excellent reproducibility. In fraction A (solubilized by urea and Nonidet P-40 (NP-40)), approximately 1300 protein spots were detected, and the relative volume (%VOL) significantly increased in five spots and significantly decreased in 10 spots in AD. The proteins identified include enzymes, molecular chaperones and cytoskeletal proteins. In …fraction B (solubilized by urea, thiourea, N-decyl-N,N-dimethyl-3-ammonio-1-propane sulfonate (SB3-10) and 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS)), over 500 protein spots were detected in the 2-DE data analysis. The %VOL of three spots was significantly increased in AD. Two of these spots were identified as glial fibrillary acidic protein (GFAP) using mass spectrometry. These results suggest that subproteomics following sequentially extracted brain proteins is a useful method for the analysis of brain extracts containing hydrophobic proteins. Our findings will prompt further study on disease-linked proteins for the investigation of AD pathogenesis and the quest for disease markers. Show more

Keywords: Alzheimer's disease, proteome, proteomics, two-dimensional gel electrophoresis

DOI: 10.3233/JAD-2004-6306

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 257-268, 2004

Authors: Shea, Thomas B. | Ortiz, Daniela | Rogers, Eugene

Article Type: Research Article

Abstract: The E4 allele of apolipoprotein E (ApoE) is associated with neurodegeneration in part due to increased oxidative stress. Transgenic mice lacking ApoE (-/-) represent a model for the consequences of deficiencies in ApoE function. Dietary deficiency in folate and vitamin E has previously been shown to potentiate the impact of ApoE deficiency; ApoE-/- mice deprived of folate and vitamin E for 1 month demonstrated increased oxidative damage in brain tissue and impaired cognitive performance as compared to ApoE+/+ mice. Since individuals homozygous for E4 can demonstrate more increased risk for neurodegeneration and an earlier age of onset than individuals heterozygous …for E4, we tested the impact of folate and vitamin E deprivation on ApoE+/- mice. Thiobarbituric acid-reactive substances in brain tissue of ApoE+/- were significantly increased compared to ApoE+/+ mice, but this increase was less than that observed in ApoE-/- mice. By contrast, livers of ApoE+/- and -/- mice displayed an identical increase over that of +/+ mice. ApoE-/- mice, but not +/- or +/+ mice, exhibited impaired cognitive performance in maze trials when deprived of folate and vitamin E. These findings support the notion that homozygous deficiency of ApoE function can be more severe than heterozygous deficiency. They further suggest that the impact of partial deficiency in ApoE function may present a latent risk that may manifest only when compounded by other factors such as dietary deficiency. Show more

Keywords: apolipoprotein E, folate, vitamin E, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-2004-6307

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 269-273, 2004

Authors: Grammas, Paula | Ottman, Todd | Reimann-Philipp, Ulrich | Larabee, Jason | Weigel, Paul H.

Article Type: Research Article

Abstract: The multifunctional serine protease thrombin has been shown to be neurotoxic in vitro and in vivo and is demonstrable in the Alzheimer disease (AD) brain. We have documented that in AD the cerebral microvasculature is a source of inflammatory and neurotoxic proteins. The objective of this study was to determine if injured brain endothelial cells could be a source of neurotoxic thrombin. Brain endothelial cells were incubated with either sodium nitroprusside (SNP, 10 μM), inflammatory proteins (IL-1β, IL-6, TNFα, LPS, IFNγ) or the PKC inhibitor bisindolymaleimide (1 μM) for 24 h and conditioned media collected. Endothelial cell conditioned medium was …incubated with purified apolipoprotein E4 (apoE4) for 24 h, and then analyzed for neurotoxic activity against primary cortical cultures and for apoE4 fragments by western blot. Endothelial cell conditioned medium collected after treatment with either SNP, inflammatory proteins, or the PKC inhibitor bisindolymaleimide, demonstrated a significant (p < 0.005) level of thrombin activity, the presence of apoE4 fragments, and was capable of evoking neuronal cell death. These data demonstrate that endothelial cell injury results in thrombin release and suggest that the brain microcirculation could be a source of neurotoxic factors in AD. Show more

Keywords: thrombin, apolipoprotein E, neurotoxin, brain endothelium, Alzheimer's disease

DOI: 10.3233/JAD-2004-6308

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 275-281, 2004

Authors: Deignan, Marguerite E. | Prior, Marguerite | Stuart, Lorraine E. | Comerford, Emma J. | McMahon, Hilary E.M.

Article Type: Research Article

Abstract: Central to Prion diseases is the normal endogenous Prion protein, PrPC . In spite of years of research the exact function of this protein remains enigmatic. Numerous binding partners have been identified for PrPC and due to the presence of a repeated sequence of PHGGGWGQ in the proteins amino-terminus it can bind metal ions. The protein is a complex molecule and each portion of PrPC possesses different roles for function and/ or trafficking. As understanding the role of PrPC is central to these disorders the structure/function relationship will be reviewed here.

Keywords: prion, carboxyl-terminus, amino-terminus, copper, glycosylation

DOI: 10.3233/JAD-2004-6309

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 283-289, 2004

Authors: House, Emily | Collingwood, Joanna | Khan, Ayesha | Korchazkina, Olga | Berthon, Guy | Exley, Christopher

Article Type: Research Article

Abstract: Metals are found associated with β-pleated sheets of Aβ42 in vivo and may be involved in their formation. Metal chelation has been proposed as a therapy for Alzheimer's disease on the basis that it may safely dissolve precipitated Aβ peptides. We have followed fibrillisation of Aβ42 in the presence of an additional metal ion (Al(III), Fe(III), Zn(II), Cu(II)) over a period of 32 weeks and we have investigated the dissolution of these aged peptide aggregates in the presence of both desferrioxamine (DFO) and ethylenediaminetetraacetic acid (EDTA). Aβ42 either alone or in the presence of Al(III) or Fe(III) …formed β-pleated sheets of plaque-like amyloids which were dissolved upon incubation with either chelator. Zn(II) inhibited whilst Cu(II) prevented the formation of β-pleated sheets of Aβ42 and neither of these influences were affected by incubation of the aged peptide aggregates with either DFO or EDTA. Freshly prepared solutions of Aβ42 either alone or in the presence of added Al(III) or Fe(III) did not form β-pleated amyloid in the presence of DFO when incubated for up to 8 weeks. EDTA did not prevent β-pleated amyloid formation in the same treatments and promoted β-pleated amyloid formation in the presence of either Zn(II) or Cu(II). The presence of significant concentrations of Al(III) and Fe(III) as contaminants of 'Aβ42 only' preparations suggested that both of these metals were involved in either triggering the formation or stabilising the structure of β-pleated amyloid. If the formation of such amyloid is critical to the aetiology of AD then the chelation of Al(III) and Fe(III) may prove to be a protective mechanism whilst the chelation of Cu(II) and Zn(II) without also chelating Al(III) and Fe(III) might actually exacerbate the condition. Show more

Keywords: Aβ42, amyloid, aluminium, iron, zinc, copper, chelation, Alzheimer's disease

DOI: 10.3233/JAD-2004-6310

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 291-301, 2004

Authors: LeVine, III, Harry

Article Type: Research Article

Abstract: The second generation of therapeutic strategies for Alzheimer's disease (AD) embraces the Amyloid Hypothesis, which asserts that through a series of events not completely understood, misfolding of the amyloid-β (Aβ) peptide is a primary event eliciting neurodegeneration and AD pathology. A variety of approaches are being tried to interrupt the disease process, including reducing the production of the Aβ peptide, inhibiting its aggregation, and promoting its removal, for example via immunotherapy. The success of anti-Aβ disease-modifying approaches in eliminating the postulated etiologic form(s) of the peptide will ultimately depend on biological clearance and degradation of the various forms of the …Aβ peptide from the brain compartment. Little is known about exchange of theβ peptide between the brain and blood. Increased understanding of this process in experimental animal models and humans, and how it changes with aging, will likely open new therapeutic avenues. It will also be needed to properly design early clinical trials to verify the efficacy of potential drug candidates working through the Aβ peptide. Show more

Keywords: oligomer, proteolysis, aging, misfolded proteins, deposition, peripheral sink

DOI: 10.3233/JAD-2004-6311

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 303-314, 2004

Authors: Miu, Andrei C. | Olteanu, Adrian I. | Miclea, Mircea

Article Type: Research Article

Abstract: The persistence of neuroscientists in exploring aluminium's (Al) possible contribution to the pathogenesis of Alzheimer's disease (AD) has resulted in a wealth of researches detailing the biological toxicity of this metal. However, to date, there have been few accounts of the interference of Al with aging and its relevance to the pathogenesis of AD. We investigated the behavioral and the ultrastructural signatures of Al in the hippocampus on young and aging rats which were exposed for three months to aluminium gluconate. The aging animals displayed decreased scores of activity and emotionality, and the Al-exposed aging males had altered emotional reactivity …behaviors. The electron-microscopic analysis indicated that Al promoted in the aging hippocampus a variety of cellular and ultrastructural degenerative signs, such as granulo-vacuolar degenerations, deposition of lipofuscin and amyloid in the cytoplasm of neurons and astrocytes, and in extracellular compartments, Hirano bodies, demyelination and the atrophy of the mitochondria. Moreover, the quantitation of myelin sheath width and the diameter of mitochondria measured on randomly selected samples confirmed that myelin and mitochondria are primary targets of Al's toxicity. Demyelination and mitochondrial atrophy seemed more advanced in the hippocampus of Al-exposed aging males, supporting the effect of sex suggested by the behavioral results. These findings and other collateral results also reported here are discussed in the context of a possible involvement of Al in AD, mediated by aging and catalyzed by hepatic morphopathology. Show more

Keywords: aluminum, aging, mitochondria, myelin, Alzheimer's disease

DOI: 10.3233/JAD-2004-6312

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 315-328, 2004

Authors: Flicker, L. | Martins, R.N. | Thomas, J. | Acres, J. | Taddei, K. | Norman, P. | Jamrozik, K. | Almeida, O.P.

Article Type: Research Article

Abstract: The ε4 allele of apolipoprotein E (APOE), and the plasma levels of APOE, amyloid β-protein precursor, amyloid β1-40 (Aβ40) and homocysteine (Hcy) have all been correlated with the presence of dementia. Mutations in the methylnetetrahydrofolate reductase enzyme (MTHFR) have been associated with elevated levels of Hcy. This study explored the association of these factors with cognition and depression in community dwelling older men. Two hundred and ninety-nine men, mean age 78.9 years (SD 2.8), were studied in this cross-sectional survey. Mean plasma Hcy was 13.5 (SD 5.3) μmol/L. The MTHFR genotype had no obvious impact on Hcy levels. Ln …Hcy and Ln Aβ40 were both inversely correlated with calculated glomerular filtration rate (cGFR), r = -0.41 (p < 0.001) and r = -0.28 (p < 0.001), respectively. There was a positive correlation between Ln Hcy and Ln Aβ40, r = 0.19 (p < 0.001), which remained significant after adjusting for cGFR, with a doubling of Hcy associated with a 24% increase of Aβ40. The e4 allele was associated with increased depressive symptoms as measured by the Geriatric Depression Scale-15, Odds ratio (OR) = 2.59 (95%CI 1.06–6.34) and poorer performance on the Clock Drawing Test, OR = 2.32 (95% CI: 1.25–4.29). There was a positive association between Aβ40 and Hcy, even after adjustment for cGFR in this sample of well, community dwelling older men. This association may help elucidate the link between elevated levels of Hcy and Alzheimer's disease. Show more

Keywords: dementia, amyloid protein, Apolipoprotein E, cognition, depression, homocysteine, methylnetetrahydrofolate reductase, geriatric

DOI: 10.3233/JAD-2004-6313

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 329-336, 2004

Article Type: Discussion

DOI: 10.3233/JAD-2004-6314

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 337-342, 2004

Article Type: Other

DOI: 10.3233/JAD-2004-6315

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 343-343, 2004

Article Type: Obituary

DOI: 10.3233/JAD-2004-6316

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 345-345, 2004

Article Type: Announcement

DOI: 10.3233/JAD-2004-6317

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 347-352, 2004