| Volume 1, Number
6, December 1999
Pages 353-360
Thomas B. Shea and Fatma J. Ekinci
Biphasic Effect of Calcium Influx on Tau
Phosphorylation: Involvement of Calcium-Dependent Phosphatase and
Kinase Activities
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 1µM calcium ionophore A23187 in the
presence of 0.1mM extracellular calcium depleted phospho-tau levels
within 30min. However, extending ionophore treatment to 60min 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 (3µM) and extracellular calcium (0.9mM). 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.
Pages 361-378
Juan Ramón Muñoz-Montaño, Filip Lim, Francisco
J. Moreno, Jesús Avila and Javier Díaz-Nido
Glycogen Synthase Kinase-3 Modulates
Neurite Outgrowth in Cultured Neurons: Possible Implications for
Neurite Pathology in Alzheimer´s Disease
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.
Pages 379-386
Garth F. Hall (communicated by Thomas Shea)
PHF-Tau from Alzheimer Brain is Rapidly
Dephosphorylated and Degraded When Injected Into Neurons In Situ
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.
Pages 387-407
Christoph Schmitz, Susanne Materne and Hubert
Korr
Cell-Type-Specific Differences in
Age-Related Changes of DNA Repair in the Mouse Brain - Molecular
Basis for a New Approach to Understand the Selective Neuronal
Vulnerability in Alzheimer's Disease
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.
Pages 409-417
Kelly L. Jordan-Sciutto, Kathleen Morgan, and
Robert Bowser
Increased cyclin G1 immunoreactivity during
Alzheimer's disease
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.
Pages 419-424
B. Van Everbroeck, A.J.E. Green, Ph. Pals, J.J. Martin, P. Cras
Decreased levels of amyloid ß 1-42 in cerebrospinal fluid of
Creutzfeldt-Jakob disease patients.
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 ß
1-42 (Aß1-42). 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. Aß1-42
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 Aß1-42 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 Aß1-42 levels in CSF
of CJD patients. No clear correlation between them was found in this
series. This signifies that the deceased Aß1-42 levels in CSF are
not just due to plaque retention but that others mechanisms must
also play a role.
Page 425
Book Review: Daniel Kuhn, MSW; Alzheimer's Early Stages:
First Steps in Caring and Treatment, Hunter House Publisher, 1999,
Alameda, CA, 274 pp.
Reviewed by Robert P. Friedland
Page 426
List of Reviewers
Page 427-430
Author Index of Volume 1
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