Journal of Alzheimer's Disease - Volume 1, issue 6

Authors: Shea, Thomas B. | Ekinci, Fatma J.

Article Type: Research Article

Abstract: Conflicting data has emerged documenting decreased and increased levels of phospho-tau following calcium influx.  Calcium influx achieved by treatment of SH-SY-5Y human neuroblastoma with 1 µM calcium ionophore A23187 in the presence of 0.1 mM extracellular calcium depleted phospho-tau levels within 30 min. However, extending ionophore treatment to 60 min raised phospho-tau levels beyond that of control levels. Total tau levels were unchanged throughout these treatments, indicating that the reduction in PHF-1 reflected sequential alterations in tau phosphorylation rather than total tau.  More rapid accumulation of phospho-tau accompanied treatment with increased concentrations of ionophore (3 µM) and extracellular calcium (0.9 mM).  An inhibitor active against calcium-dependent kinase(s) prevented the …increase in phospho-tau following calcium influx.  These data underscore that phospho-tau levels represent the summation of kinase and phosphatase activities and indicate that net dephosphorylation or phosphorylation is dependent upon the extent and/or rate of calcium influx Show more

Keywords: tau, calcium influx, phosphorylation, kinases, phosphatases, calcium-dependent, neurodegeneration, paired helical filaments, Alzheimer's disease

DOI: 10.3233/JAD-1999-1601

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 353-360, 1999

Authors: Muñoz-Montaño, Juan Ramón | Lim, Filip | Moreno, Francisco J. | Avila, Jesús | Díaz-Nido, Javier

Article Type: Research Article

Abstract: Glycogen synthase kinase-3 (GSK-3) is thought to play an important role in the hyperphosphorylation of tau, and possibly other proteins, in Alzheimer's disease (AD). However, the effects of GSK-3 on neuronal metabolism are still largely unknown. Here we describe that a low concentration of lithium, which can partially inhibit endogenous GSK-3, favored the extension of neurites from developing neurons, whereas a high concentration of lithium impaired neurite growth. Furthermore, the overexpression of exogenous active GSK-3 in neurons by infection with a defective herpesviral vector blocked neurite growth, which was not affected by either expression of inactive GSK-3 or just the …herpesviral vector infection. Neurite extension was restored when neurons overexpressing exogenous active GSK-3 were incubated with lithium. These results are consistent with a role for GSK-3 in the regulation of cytoskeletal dynamics during neurite growth. Accordingly, up-regulation of GSK-3 may contribute to cytoskeletal pathology within neurites in AD. Show more

DOI: 10.3233/JAD-1999-1602

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 361-378, 1999

Authors: Hall, Garth F.

Article Type: Research Article

Abstract: Accumulation of abnormally modified tau protein (PHF-tau) is the principal intracellular lesion in a variety of neurodegenerative diseases, including Alzheimer's Disease (AD), but the cellular mechanisms underlying this accumulation are unknown. In this study, the cellular metabolism of PHF-tau purified from AD brain was investigated by microinjecting it into identified central neurons of the lamprey, a lower vertebrate. Dephosphorylation of 2 critical epitopes (the PHF-1 and TAU-1 sites), occurred within a few hours of PHF-tau microinjection, while proteolysis was complete by 2 days. These results constitute the first demonstration of the intracellular degradation of PHF-tau in an experimental in vivo …system and suggest that the degradation of PHF-tau in situ is preceded by dephosphorylation. They also suggest that intracellular PHF-tau accumulation is primarily due to the failure of normal dephosphorylation and/or proteolytic mechanisms during neurofibrillary degenerative disease. Show more

Keywords: in vivo model, vertebrate CNS, PHF-tau proteolysis, microinjection, dephosphorylation

DOI: 10.3233/JAD-1999-1603

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 379-386, 1999

Authors: Schmitz, Christoph | Materne, Susanne | Korr, Hubert

Article Type: Research Article

Abstract: Despite intensive research over the last decades, the molecular basis of the selective neuronal vulnerability in Alzheimer's disease (AD) is still largely unknown. In this context we have recently shown by means of quantitative autoradiography that presumably all types of neurons in the mouse brain suffer an age-related decrease in the rate of mitochondrial DNA synthesis, while in contrast only some distinct types of neurons showed a decrease in the rate of spontaneous overall nuclear DNA repair measured as unscheduled nuclear DNA synthesis. Most strikingly, there was a highly positive correlation to be found between that group of neurons in …the mouse brain showing the age-related decrease in the rate of spontaneous overall nuclear DNA repair (pattern X) and the pattern of neurons in the human brain which – according to the literature – are affected by the formation of neurofibrillary tangles in AD (pattern Y). To minimize the risk that this correlation was a result of mere chance based on the selection of the nine types of neurons investigated thus far, in the present study nine further types of neurons in phylogenetically different regions of the mouse brain were investigated by using the same method. An age-related decrease in the rate of spontaneous overall nuclear DNA repair was found only for projection neurons of brain areas with a more plastic, variable and/or malleable structure over phylogenesis but neither for projection neurons of brain areas with a more rigid, invariant and/or conservative structure over phylogenesis nor for interneurons. The obtained results confirmed the highly positive correlation between the aforementioned patterns X and Y. Together with a wealth of data from the literature regarding age-related neuron loss in both the rodent and the human brain, these results may indeed indicate a new approach for understanding the selective neuronal vulnerability in AD. Show more

Keywords: aging , mouse, mitochondria, DNA repair, autoradiography, Alzheimer's disease

DOI: 10.3233/JAD-1999-1604

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 387-407, 1999

Authors: Jordan-Sciutto, Kelly L. | Morgan, Kathleen | Bowser, Robert

Article Type: Research Article

Abstract: Numerous proteins are alternatively expressed in neurons and glia during Alzheimer's disease (AD) and may contribute to the regulation of neuronal cell death or function in regenerative responses to neuronal injury. A recently described member of the cyclin gene family, cyclin G1, is expressed in post-mitotic neurons in the adult rat brain and is expressed at high levels after brain injury. In the current study we examined the expression and subcellular distribution of cyclin G1 in non-demented adult and AD brain. While low levels of cyclin G1 protein were observed in pyramidal neurons in control brain, abundant cyclin G1 immunoreactivity …was present in the cytoplasm of pyramidal neurons in the neocortex and hippocampus of AD brain. Cyclin G1 immunoreactivity was not present in cells containing neurofibrillary pathology. Our results indicate that cyclin G1 is expressed in human adult brain and exhibits increased immunoreactivity in the cytoplasm of pyramidal neurons in AD. In addition, cyclin G1 immunoreactivity was not evident in cells containing cytoskeletal pathology. Show more

DOI: 10.3233/JAD-1999-1605

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 409-417, 1999

Authors: Van Everbroeck, B. | Green, A.J.E. | Pals, Ph. | Martin, J.J. | Cras, P.

Article Type: Research Article

Abstract: Creutzfeldt–Jakob disease (CJD) is a rare neurodegenerative disease caused by the prion protein. In the search for biochemical markers for CJD, cerebrospinal fluid (CSF) of 101 patients was analysed for 14-3-3 protein, hTau-protein and amyloid-β 1-42 (Aβ1-42 ). The 14-3-3 test had a specificity of 91.5% and a sensitivity of 84%. The hTau test resulted in 95% specificity and 74% sensitivity, when a cut-off of 1530 pg/ml was used. Aβ1-42 detection in CSF of 29 probable or definite CJD patients revealed significantly decreased values (p = 0.01) compared to a group of 22 neurological controls. In the CJD patients a mean of …319 ± 102 pg/ml was found. In the neurological control group a mean of 553 ± 268 pg/ml was observed. In patients with a false positive 14-3-3 test (n = 5) a mean of 716 ± 441 pg/ml was found. We conclude that determination of Aβ1-42 levels in CSF can be useful for identifying false positive 14-3-3 results in suspected CJD patients. We also compared the presence of senile plaques and the Aβ1-42 levels in CSF of CJD patients. No clear correlation between them was found in this series. This signifies that the deceased Aβ1-42 levels in CSF are not just due to plaque retention but that other mechanisms must also play a role. Show more

Keywords: ELISA, dementia, amyloid, Alzheimer's disease , 14-3-3 protein, hTau-protein,

DOI: 10.3233/JAD-1999-1606

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 419-424, 1999

Authors: Friedland, Robert P.

Article Type: Book Review

DOI: 10.3233/JAD-1999-1607

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 425-425, 1999

Article Type: Other

DOI: 10.3233/JAD-1999-1608

Citation: Journal of Alzheimer's Disease, vol. 1, no. 6, pp. 426-426, 1999