Journal of Alzheimer's Disease - Volume 12, issue 4

Authors: Vardy, Emma R.L.C. | Rice, Penny J. | Bowie, Peter C.W. | Holmes, John D. | Grant, Peter J. | Hooper, Nigel M.

Article Type: Research Article

Abstract: Background: Insulin-like growth factor (IGF)-1 has been implicated in the pathogenesis of Alzheimer's disease (AD). Methods: We compared the level of circulating total and bioavailable IGF-1, by simultaneous measurements of IGF-1 and IGF binding protein (IGFBP)-3, between 87 patients diagnosed with AD and 126 age and sex matched control subjects without cognitive impairment. Blood samples were collected and IGF-1 and IGFBP-3 measured by ELISA. Subjects were also genotyped for apolipoprotein E. Results: Total circulating IGF-1 levels were significantly raised in the AD group as compared to the control group (p = 0.022 ). There …was no significant difference in the circulating level of IGFBP-3 between the two groups. When the IGF-1 levels were ratioed against IGFBP-3 levels as an indicator of unbound, bioavailable circulating IGF-1, there was a significant increase in the molar IGF-1:IGFBP-3 ratio in the AD subjects (0.181 ± 0.006) as compared to the controls (0.156 ± 0.004) (p < 0.001 ). Logistic regression analysis revealed that an increase in the IGF-1:IGFBP-3 molar ratio increased the risk of AD significantly. Conclusion: The results of increased total and free circulating IGF-1 support the hypothesis that in its early stages late-onset AD reflects a state of resistance to IGF-1. Show more

Keywords: Alzheimer's, insulin-like growth factor-1, insulin-like growth factor binding protein-3, apolipoprotein E, insulin resistance

DOI: 10.3233/JAD-2007-12401

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 285-290, 2007

Authors: Grünblatt, Edna | Zander, Nicole | Bartl, Jasmin | Jie, Li | Monoranu, Camelia-Maria | Arzberger, Thomas | Ravid, Rivka | Roggendorf, Wolfgang | Gerlach, Manfred | Riederer, Peter

Article Type: Research Article

Abstract: Sporadic Alzheimer's (AD) and Parkinson's disease (PD) are late-onset neurodegenerative diseases with tremendous impact on lives of affected individuals. There is a great probability of developing concurrent Parkinsonism in AD and vice-versa than would be predicted by independent prevalence of each disease. We hypothesize that in sporadic AD as well as PD a combination of environmental effects and gene expression may affect specific brain areas leading to neurodegeneration. We profiled gene expression of AD compared to PD and age matched controls post-mortem in the hippocampus, the gyrus-frontalis-medius (Gfm) and the cerebellum using Gene-Chip microarray (Affymetrix) and quantitative-real-time-RT-PCR. Twelv genes altered …in similar manner in AD and PD, while four genes showed differential expression profiles between AD and PD in different brain regions (cannabinoid-receptor-2, Histone-cluster-1-H3e, nicotinic-cholinergic-receptor-α6 and β-site-APP-cleaving enzyme-1). Knowledge of selective gene expression profile can lead to better understanding of disease pathology and development of specific diagnosis and effective therapy. Show more

Keywords: Alzheimer's disease, affymetrix, gene chip, gene expression, microarray, Parkinson's disease, Quantitative-RT-PCR

DOI: 10.3233/JAD-2007-12402

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 291-311, 2007

Authors: Exley, Christopher

Article Type: Letter

DOI: 10.3233/JAD-2007-12403

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 313-315, 2007

Authors: Takshima, Akihiko

Article Type: Research Article

DOI: 10.3233/JAD-2007-12404

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 317-318, 2007

Authors: Drever, Benjamin D. | Anderson, William G.L. | Johnson, Helena | O'Callaghan, Matthew | Seo, Sangwon | Choi, Deog-Young | Riedel, Gernot | Platt, Bettina

Article Type: Research Article

Abstract: The non-competitive NMDA receptor antagonist memantine, currently prescribed for the treatment of Alzheimer's disease, is assumed to prevent the excitotoxicity implicated in neurodegenerative processes. Here, we investigated the actions of memantine on hippocampal function and signalling. In behavioural experiments using the water maze, we observed that memantine (at 2 mg/kg) reversed scopolamine-induced learning deficits in mice. When acutely applied to mouse hippocampal slices, memantine caused a significant upward shift in the population spike input-output relationship at 10 and 100 μM, and a corresponding downward shift in latency, indicative of overall enhanced synaptic transmission. This action was blocked by the muscarinic …antagonist scopolamine (10 μM) but not by the NMDA antagonist MK-801 (10 μM) or the GABA antagonist bicuculline (20 μM). Further, memantine occluded potentiation induced by 50 nM carbachol (CCh), while enhancing inhibitory actions of CCh at 1 μM, suggesting additive actions. As anticipated for an NMDA antagonist, 100 μM (but not 10 μM) memantine also inhibited tetanus-induced long-term potentiation (LTP), and NMDA-induced Ca2+ signals were blocked in cultured hippocampal neurones at 10 μM (by 88%). Overall, our data suggest actions of memantine beyond NMDA receptor antagonism, including stimulating effects on cholinergic signalling via muscarinic receptors. These interactions with the cholinergic system are likely to contribute to memantine's therapeutic potential. Show more

Keywords: Alzheimer's disease, NMDA, neuroprotection, learning, synaptic transmission, LTP, acetylcholine, muscarinic

DOI: 10.3233/JAD-2007-12405

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 319-333, 2007

Authors: Qi, Ji-ping | Wu, He | Yang, Yi | Wang, Dan-dan | Chen, Yan-xi | Gu, Yun-he | Liu, Tao

Article Type: Research Article

Abstract: Growing evidence suggests a synergistic and perhaps etiological relationship between vascular disease and Alzheimer's disease (AD), which is characterized by the progressive accumulation of amyloid-β peptide (Aβ). Moreover, apolipoprotein E (ApoE) has also been shown to be associated with AD and cerebral ischemia. It seems that cerebral ischemia may play an important, both direct and indirect, role in the pathogenesis of AD. We investigated the expression and distribution of Aβ1–40, β1–42 and ApoE in human hippocampus after cerebral ischemia in this study to determine the role of cerebral ischemia in Alzheimer's disease. Our study has demonstrated that the accumulation of …both Aβ1–40 and β1–42 were increased dramatically and consistently after cerebral ischemia. Neuronal ApoE immunoreactivity was also significantly increased in all ischemic groups compared with controls. The most likely stimulus for the increased Aβ1–40, Aβ1–42 and ApoE immunoreactivity in the CA1 and CA3 neurons is the ischemic conditions, and their upregulation, in turn, may partly explain the contribution of cerebral ischemia to the pathogenesis of AD. Therefore our observations provide a basis for establishing therapeutic strategies aimed at preventing ischemic insults and subsequent neurodegeneration in AD. Show more

Keywords: Cerebral ischemia, amyloid-β, apolipoprotein E, Alzheimer's disease, human hippocampus

DOI: 10.3233/JAD-2007-12406

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 335-341, 2007

Authors: Castellani, Rudy J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2007-12407

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 343-344, 2007

Authors: Barrantes, Alejandro | Rejas, María T. | Benítez, María J. | Jiménez, Juan S.

Article Type: Research Article

Abstract: Alzheimer's disease is a form of senile mental disorder characterized by the presence of extracellular plaques, containing amyloid-β (Aβ) as the main component. According to the amyloid hypothesis, an increase of extracellular Aβ production is in the origin of the aberrant plaques causing neuronal loss and dementia. However, a wealth of evidence has been accumulated pointing to the toxicity of soluble intracellular Aβ, having different morphologies of aggregation, as the origin of the neurodegenerative process. The exact nature of the initial molecular events by which Aβ exerts its neurotoxicity, remains obscure. Different forms of soluble Aβ peptide aggregates have been …recently found to reside in the nucleus of CHO cells and Alzheimer's disease brain samples. This paper focus mainly on the interaction between DNA and the 42 residue Aβ (Aβ42) as studied by Surface Plasmon Resonance. Electronic microscopy and UV-visible spectroscopy are also used to further characterize the interaction. Particular attention is paid to the extent of Aβ42 aggregation needed to observe the interaction with DNA. Our results show that DNA binds all soluble aggregate forms of Aβ42, therefore suggesting that DNA binding is a general property of different soluble forms of Aβ42, unrelated to the extent of aggregation. Show more

Keywords: Protein aggregation and interaction, neurotoxicity, mental disease

DOI: 10.3233/JAD-2007-12408

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 345-355, 2007

Authors: Zeng, Yang | Miao, Fei | Li, Liang | Sun, De-Hua | Xu, Xiang-Min

Article Type: Research Article

Abstract: The variants of apolipoprotein E (apoE) are closely related to hyperlipidemia III, Alzheimer's disease (AD), coronary artery disease (CAD) and many other human lipid metabolism-related problems. A rapid and accurate genotyping method specific for polymorphisms of the APOE gene is needed for population screening as well as diagnosis of apoE-related diseases in both the research and clinical setting. A polymerase chain reaction (PCR) method was designed to generate a 191-bp amplicon, which contains two common polymorphisms located in codons 112 and 158 of exon 4 of the APOE gene. The PCR amplicons for each sample were subjected to denaturing high-performance …liquid chromatography (DHPLC) analysis, which was performed under partially denaturing conditions as determined by profiling the mixture of a tested sample and a homozygous standard control amplicon at the given ratio. A total of 297 DNA samples from Chinese population were enrolled to evaluate the specificity of the assay. A blinded validation study was then performed on 130 samples randomly selected from each of the six genotype groups as determined by DHPLC profiling. The genotypes obtained with the DHPLC method were in full agreement with those obtained by direct sequencing (130/130). We have developed a PCR/DHPLC genotyping assay capable of simultaneously determining all six genotypes of APOE gene in unknown test samples at one time. Show more

Keywords: Heteroduplex, homoduplex, genotyping, pharmacogenetics, Alzheimer's disease, coronary artery disease

DOI: 10.3233/JAD-2007-12409

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 357-363, 2007

Authors: Luna-Muñoz, José | Chávez-Macías, Laura | García-Sierra, Francisco | Mena, Raúl

Article Type: Research Article

Abstract: Neurofibrillary tangles (NFT) and dystrophic neurites represent dense cytoplasmic accumulations of abnormal polymers in the brain of patients with Alzheimer's disease (AD). These polymers are referred to as paired helical filaments (PHFs) whose main structural core is composed of tau protein. Tau processing has been associated with hyperphosphorylation and truncation that results in PHF assembly. Both molecular events appear to cause conformational change of tau molecules [11,17,32]. In this regard, in a previous work focused on the analysis of patterns of immunolabeling in pre-tangle cells, we found that regional changes precede the structural modifications in tau [32]. In the present …study, we further analyzed the early stages of tau processing in pre-tangle cells by using a variety of immunological markers of specific N-terminus phosphorylation tau sites. We used AT100, TG-3, AT8, pT231, Alz-50, Tau-C3 and 423 antibodies that recognize different abnormal tau epitopes in AD brains. These antibodies were combined and analyzed using a confocal microscope. Our results indicate that the early stages of abnormal tau processing are characterized by a sequential appearance of specific phospho-dependent epitope. The cascade of appearance of the antibodies is: pT231 → TG-3 → AT8 → AT100 → Alz-50. In addition; truncation at Asp-421 of the C-terminus of tau protein, as detected by Tau-C3, is also an early molecular event in tau protein aggregation prior to PHF formation in AD. Show more

Keywords: Alzheimer's disease, paired helical filament formation, tau protein, hyperphosphorylation, conformational changes

DOI: 10.3233/JAD-2007-12410

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 365-375, 2007

Authors: Tremblay, Cyntia | Pilote, Mireille | Phivilay, Alix | Emond, Vincent | Bennett, David A. | Calon, Frédéric

Article Type: Research Article

Abstract: We report a post mortem biochemical analysis of amyloid-β (Aβ) (ELISA) and tau (Western immunoblots) in the temporo-parietal neocortex of subjects with a clinical diagnosis of mild cognitive impairment (MCI, n = 12 ), Alzheimer's disease (AD, n = 12 ) or no cognitive impairment (NCI, n = 12 ). Levels of Aβ42 in the detergent-insoluble protein fractions were significantly higher in persons with AD but did not differentiate individuals with MCI. Conversion of tau into its insoluble form (soluble/insoluble tau ratio) or into paired helical filament tau (PHFtau ) were the …biochemical variables most closely related to clinical and neuropathological diagnoses, but they did not distinguished MCI from the two other groups. Interestingly, soluble/insoluble total tau ratio, PHFtau and insoluble Aβ42 concentrations in the cortex correlated strongly with global cognition scores proximate to death and with immunohistochemical and histological quantification of Aβ and tau pathologies. Our data suggest that 1) insoluble Aβ42 and insoluble tau (total or PHFtau ) show a significant relationship with the clinical and neuropathological diagnosis of AD; 2) Although MCI appears to represent an intermediate stage between NCI and AD, the quantification of cortical Aβ and tau pathologies did not significantly distinguish subjects with MCI from either group. Show more

Keywords: Mild cognitive impairment, Alzheimer's disease, amyloid-β, tau, paired helical filament tau, postmortem, brain cortex, western immunoblotting, Elisa

DOI: 10.3233/JAD-2007-12411

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 377-390, 2007

Article Type: Announcement

DOI: 10.3233/JAD-2007-12412

Citation: Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 391-392, 2007