| Volume
12, Number 4, December 2007
Pages 285-290
Emma R. L. C. Vardy, Penny J. Rice, Peter C. W. Bowie, John D. Holmes, Peter J. Grant, Nigel M. Hooper (Communicated by Suzanne de la Monte)
Increased circulating insulin-like growth factor-1 in late-onset Alzheimer's disease
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.
Pages 291-311
Edna Grünblatt, Nicole Zander, Jasmin Bartl, Li Jie, Camelia-Maria Monoranu, Thomas Arzberger, Ravid Rivka, Wolfgang Roggendorf, Manfred Gerlach, Peter Riederer (Communicated by Christian Jacob)
Comparison analysis of gene expression patterns between sporadic Alzheimer's and Parkinson's disease
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.
Supplementary Data for Grünblatt et al. article.
Letter to the Editor
Pages 313-315
Christopher Exley
Aluminium, tau and Alzheimer's disease
Letter to the Editor
Pages 317-318
Akihiko Takshima
Study of aluminum on the pathology of Alzheimer’s disease: In vitro versus in vivo evidence
Pages 319-333
Benjamin D. Drever, William G.L. Anderson, Helena Johnson, Matthew O’Callaghan, Sangwon Seo, Deog-Young Choi, Gernot Riedel, Bettina Platt (Communicated by David Carpenter)
Memantine acts as a cholinergic stimulant in the mouse hippocampus
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 2mg/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 (10μM) but not by the NMDA antagonist MK-801 (10μM) or the GABA antagonist bicuculline (20μM). 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, 100μM (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.
Pages 335-341
Ji-ping Qi*, He Wu*, Yi Yang*, Dan-dan Wang,Yan-xi Chen, Yun-he Gu, Tao Liu; *These authors contributed equally to this study (Communicated by Dengshun Wang)
Cerebral ischemia and Alzheimer's disease: the expression of amyloid-β and apolipoprotein E in human hippocampus
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, Aβ1-42 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 Aβ1-42 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.
Commentary
Pages 343-344
Rudy J. Castellani
Vascular dementia and Alzheimer’s disease: A waning dichotomy
Pages 345-355
Alejandro Barrantes, María T. Rejas, María J. Benítez, Juan S. Jiménez (Communicated by Jesús Avila)
Interaction between Alzheimer’s Aβ1-42 peptide and DNA detected by Surface Plasmon Resonance
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 residues Aβ fragment (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 aggregates forms of Aβ42, therefore suggesting that DNA binding is a general property of different soluble forms of Aβ42, unrelated to the extent of aggregation.
Pages 357-363
Yang Zeng, Fei Miao, Liang Li, De-Hua Sun, Xiang-Min Xu
A rapid and accurate DHPLC assay for determination of apolipoprotein E genotypes
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.
Pages 365-375
José Luna-Muñoz, Laura Chávez-Macías, Francisco García-Sierra, Raúl Mena
Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease
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. 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. 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.
Pages 377-390
Cyntia Tremblay, Mireille Pilote, Alix Phivilay, Vincent Emond, David A. Bennett, Frédéric Calon (Communicated by Alexandre Valério de Mendonça)
Biochemical characterization of Aβ and tau pathologies in mild cognitive impairment and Alzheimer disease
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 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 distinguished subjects with MCI from either group.
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