Journal of Alzheimer's Disease - Volume 3, issue 5

Authors: Lidström, A-M. | Hesse, C. | Rosengren, L. | Fredman, P. | Davidsson, P. | Blennow, K.

Article Type: Research Article

Abstract: The protein clusterin has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Its expression is increased in brain regions affected by AD pathology, and to elucidate if there is a concomitant increase of clusterin also in the cerebrospinal fluid (CSF) in different neurological disorders, CSF samples from patients with AD, vascular dementia (VAD), Parkinson's disease (PD), and controls were analysed. Also longitudinal (five occasions) samples from patients with acute stroke were analysed, to follow any degenerative/regenerative phase after acute brain damage. However, there were no changes in CSF-clusterin levels from patients in AD, VAD, PD or …acute stroke, as compared to controls. The increase of clusterin in brain tissue is suggested to reflect a regenerative response process, which here is shown not to be followed by a concomitant increase in the CSF. Thus, CSF-clusterin can not be used as an indicator or a diagnostic marker for AD. Show more

Keywords: Alzheimer's disease, clusterin, apolipoprotein J, SP-40,40, dementia, regeneration, cerebrospinal fluid

DOI: 10.3233/JAD-2001-3501

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 435-442, 2001

Authors: Moreno-Herrero, Fernando | Valpuesta, José M. | Pérez, Mar | Colchero, Jaime | Baró, Arturo M. | Avila, Jesús | Garcini, Esteban Montejo de

Article Type: Research Article

Abstract: The structure of the Paired Helical filaments (PHF), a polymer of the microtubule associated protein tau, has been studied by Atomic Force Microscopy (AFM) and by cryoelectron microscopy. Mica and graphite were used as substrates in the AFM analysis with no differences in the results. A banding pattern of 8–12 nm width within the helical structure is found when detailed analysis of the data is performed. High AFM resolution images obtained by using an ultra sharp tip confirm the previous results and suggest that the structures observed are compatible with a helical ribbon made up of two parallel strands. These …results were confirmed by cryoelectron microscopy experiments. Show more

Keywords: tau protein, assembly, neurodegeneration, Alzheimer's disease, Atomic Force Microscopy, Cryoelectron microscopy

DOI: 10.3233/JAD-2001-3502

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 443-451, 2001

Authors: Ruben, George C.

Article Type: Article Commentary

DOI: 10.3233/JAD-2001-3503

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 453-454, 2001

Authors: Goux, Warren J. | Liu, Bingcam | Shumburo, Abdurahman M. | Parikh, Samir | Sparkman, Dennis R.

Article Type: Research Article

Abstract: Protease resistant paired helical filaments (prcPHF) can be isolated from the brains of Alzheimer's diseased patients. A second type of PHF, A68 PHF, may be extracted in soluble form from brain homogenate and induced to form filaments in vitro. Here we use a variety of analytical techniques to assess the protein, carbohydrate and fatty acid composition of prcPHF and A68 PHF. High-field 1 H NMR of both PHF preparations display similar fatty acid and carbohydrate proton resonances, consistent with the presence of a structurally similar glycolipid. Carbohydrate analysis showed that both preparations contained greater than 82% less than 12% C16:1 …was significantly lower in A68 PHF than in prcPHF, both preparations contained otherwise similar fatty acid profiles with the most abundant lipid component being oleic acid (C18:1, 29.3 ± 9.0%) followed by palmitic (C16:0, 28.5 ± 5.6%) 17.6 ± 7.5%) preparations revealed a profile reasonably consistent with that previously determined for PHF-tau but significantly higher in glycine and lower in lysine than would be predicted from the cDNA sequence. On a weight per cent basis, protein accounted for about 51% A68 PHF samples but only about 10% Carbohydrate and fatty acid accounted for about 39% A68 PHF samples but 74% preparations showed strong correlations between the total amount of tau protein and fatty acid. These results suggest that a glycolipid component forms an integral part of the PHF structure. Show more

Keywords: Alzheimer's disease, paired helical filaments, tau, glycolipid, NMR, GC/MS

DOI: 10.3233/JAD-2001-3504

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 455-466, 2001

Authors: Chen, Shu G.

Article Type: Article Commentary

DOI: 10.3233/JAD-2001-3505

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 467-469, 2001

Authors: Connor, J.R. | Milward, E.A. | Moalem, S. | Sampietro, M. | Boyer, P. | Percy, M.E. | Vergani, C. | Scott, R.J. | Chorney, M.

Article Type: Research Article

Abstract: Excess iron accumulation in the brain is a consistent observation in Alzheimer's Disease. Iron affects amyloid precursor protein (AβPP) processing and promotes deposition of Aβ. Iron is also among the most potent biological toxins because of its ability to react with oxygen to form reactive oxygen species. Consequently, elucidation of the mechanisms associated with maintaining brain iron homeostasis is fundamentally important to understanding the underlying pathogenesis in AD. The iron overload disorder, Hemochromatosis, is the most common genetic disorder (1:200) so a significant percentage of AD patients can be expected to carry this mutation. Heterozygotes for this mutation also have …an increased, but sub-clinical iron burden. Given the high percentage of the population who are at significant risk for iron overload, we propose that the hemochromatosis mutation be considered as a confounding factor when evaluating the contribution of genetic associations with AD and treatment strategies and efficacy. Two recent papers and new evidence presented here that the protein associated with hemochromatosis is expressed on blood vessels, choroid plexus and the ependymal cells in the brain are offered as support for this proposal. Show more

DOI: 10.3233/JAD-2001-3506

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 471-477, 2001

Authors: Ho, Rebecca | Ortiz, Daniela | Shea, Thomas B.

Article Type: Research Article

Abstract: Exposure of cultured neurons and neuronal cells to aggregated amyloid-β (Aβ) induces multiple neurodegenerative events including accumulation of cytosolic calcium, generation of reactive oxygen species, abnormal levels of phosphorylation of the microtubule-associated protein tau, and apoptosis. Prevention of accumulation of calcium within the cytosol also prevents all other events, suggesting that calcium accumulation is an early and pivotal event in Aβ neurotoxicity. Calcium influx has been suggested to occur via L voltage-sensitive calcium channels or NMDA channels. Calcium influx into differentiated human neuroblastoma cells has been previously attributed to the L voltage-sensitive calcium channel, but the contribution of the NMDA …channel was not examined. In the present study, treatment of these cells with MK-801, an antagonist of NMDA channels, failed to attenuate Aβ-induced calcium influx or neurodegeneration, while nimopridine, an antagonist of the L voltage-sensitive calcium channel, blocked Aβ-induced calcium influx. Our findings suggest that NMDA channels do not contribute significantly to Aβ neurotoxicity in these acute cell culture analyses. Show more

Keywords: amyloid, calcium, glutamate, calcium channels, neurodegeneration, Alzheimer's disease

DOI: 10.3233/JAD-2001-3507

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 479-483, 2001

Authors: Xia, Yu | Saitoh, Tsunao | Uéda, Kenji | Tanaka, Seigo | Chen, Xiaohua | Hashimoto, Makoto | Hsu, Leigh | Conrad, Chris | Sundsmo, Mary | Yoshimoto, Makoto | Thal, Leon | Katzman, Robert | Masliah, Eliezer

Article Type: Research Article

Abstract: The human NACP/α-synuclein gene has been cloned. This gene consists of 6 exons ranging in size from 42 to 1110 bp. The translation start codon ATG is encoded by exon 2 and the stop codon TAA is encoded by exon 6. The non-Aβ component of Alzheimer's disease amyloid (NAC) is encoded by exon 4. The two previously reported minor isoforms of NACP/α-synuclein, NACP112 [29] and NACP126 [6], are alternatively spliced products, in which exon 5 and exon 3 are spliced out, respectively. Exon 1 was found to have different splicing sites, producing different 5'-untranslated sequences in the cDNAs. A previously …reported dinucleotide repeat polymorphic marker has been mapped to 8kb upstream of the transcription start site. A highly TC-rich sequence in intron 4 was found to be polymorphic by length and four alleles, A0, A1, A2 and B have been identified in the Caucasian population. Genotyping this polymorphism among pure Alzheimer's, Lewy body variant and Parkinson's subjects and aged normal control subjects did not reveal any significant differences. Show more

DOI: 10.3233/JAD-2001-3508

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 485-494, 2001

Authors: Scheff, Stephen W. | Price, Douglas A.

Article Type: Research Article

Abstract: Synapse loss is considered a profound neuropathology associated with Alzheimer's disease (AD). This AD-related change in connectivity can be demonstrated in many regions of the neocortex. The posterior cingulate cortex has been identified as an area involved early in the disease process but has not been well studied. The anterior cingulate cortex, which is morphologically distinct from the posterior cingulate, is also involved in AD. The present study employed ultrastructural techniques to assess synaptic numbers in these two regions of association cortex. Both cingulate areas demonstrated a significant loss in lamina III in AD, while only the posterior cingulate manifested …a loss in lamina V. The failure to find a significant change in lamina V of the anterior cingulate may be related to its connectivity with the motor system. The heterogeneity of synaptic change in this cortical region may reflect important information concerning corticocortico connectivity changes in AD. Show more

Keywords: dementia, limbic system, aging, CNS plasticity, synaptic density

DOI: 10.3233/JAD-2001-3509

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 495-505, 2001

Authors: Feldman, H. | Gabathuler, R. | Kennard, M. | Nurminen, J. | Levy, D. | Foti, S. | Foti, D. | Beattie, B.L | Jefferies, W.A.

Article Type: Research Article

Abstract: Background: The application of formal clinical diagnostic criteria for the identification of Alzheimer's Disease (AD) has improved diagnostic sensitivity. However, there remains a need for non-invasive biological markers and laboratory tests, which can facilitate case identification, and the assessment of treatment response. The p97 protein is a secreted protein specifically expressed by amyloid plaque associated reactive microglia that may have AD diagnostic ability. Methods: A quantitative radioimmunoassay was developed to measure serum p97. This study, under a double blind protocol, evaluated the utility of serum p97 as diagnostic test for AD. All subjects were referred to the UBC …Clinic for Alzheimer’s Disease and Related Disorders (CADRD) for clinical assessment of dementia. A serum p97 sample was obtained at the time of assessment but diagnosis of disease was determined independently of p97 examination. Results: “Possible” and “probable” AD cases (n = 41) and cognitively normal controls (n = 64) showed a highly significant difference in mean p97 concentration (41 vs. 20 ng/ml, p<0.001). There was some overlap in p97 distributions between AD cases and control subjects. The area under the curve (AUC) for the receiver operator curve (ROC) was 0.812. Conclusions: These results further support the specificity of high serum p97 levels in AD and its potential utility as a biological marker in AD. The reproducible elevation of serum p97 in AD underlines the need to further determine its role as a biological marker and diagnostic adjunct for AD. Show more

DOI: 10.3233/JAD-2001-3510

Citation: Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 507-516, 2001