Volume 2, Number
1, March 2000
Pages 1-6
D.V. Micic and N.D. Petronijevic
Acetylcholinesterase Activity In The
Mongolian Gerbil Brain After Acute Treatment With Aluminum
Abstract: The aim of the present
study was to evaluate the acetylcholinesterase activity in the brain
of adult gerbils (Meriones unguiculatus) treated with aluminum. AlCl3
x 6H2O was given "per os" in the amount of 3.7 g/kg body
weight. The animals were killed 24, 48, 72 and 96 hours after the
treatment. The activities of acetylholinesterase in the
mitochondrial and microsomal fractions of cortex, hippocampus and
thalamus as well as plasma levels of aluminum were measured.
Acetylcholinesterase activity was significantly reduced in the
mitochondrial and microsomal fraction of all investigated
structures. Decrease of the enzyme activity was observed in the
first 24 hours, and it was most prominent 48 hours after the
administration of aluminum in the mitochondrial fractions when the
activity of the enzyme was 31%, 29% and 18.9% of the control value,
and after 24 hours in the microsomal fractions when the activity of
the enzyme was 43%, 48% and 32% of the control value in the cortex,
hippocampus and thalamus, respectively. Ninety six hours after the
administration of aluminum the activity of the enzyme was 63%, 57%
and 31% of the value in the control group in mitochondrial, and
100%, 80% and 73% of the control value in microsomal fractions in
cortex, hippocampus and thalamus. Plasma levels of aluminum were
significantly elevated 24 hours after administration of aluminum.
After 48 hours the values were doubled in comparison with the
control, 72 hours later plasma concentrations of aluminum were
decreased, and after 96 hours they reached the value in the control
group. We can conclude that a single oral dose (LD50) of aluminum is
responsible for the drop in brain acetylcholinesterase activity and
that the changes remain even after normalization of plasma aluminum
concentration.
Pages 7-15
Fatma J. Ekinci and Thomas B. Shea
ß-Amyloid-Induced Tau Phosphorylation Does
Not Correlate with Degeneration in Cultured Neurons
Abstract: Treatment of cultured neurons
with ß-amyloid (Aß) evokes multiple consequences, including calcium
influx, production of reactive oxygen species (ROS),
hyperphosphorylation of tau. Which of these events is the major
cause of Aß-induced neurodegeneration has been the subject of
controversy. We undertook to determine whether or not the
accumulation of hyperphosphorylated tau mediated neurodegeneration.
Murine cortical neurons demonstrated increased phospho-tau
immunoreactivity between 2-8hr after treatment of murine cortical
neurons with Aß25-35. Cultures underwent overall neurodegeneration
between 8-16hr as ascertained by phase-contrast microscopy, a
commercial “live/dead” assay and externalization of phosphatidyl
serine. Unexpectedly, however, the healthiest-appearing neurons in
with Aß–treated cultures contained relatively more phospho-tau
immunoreactivity, while obviously degenerating neurons contained
less; degenerating neurons often contained less phospho-tau
immunoreactivity than did non-Aß-treated control neurons. By
contrast, accumulation of reactive oxygen species, previously
demonstrated to mediate Aß-induced neurodegeneration, was most
prominent within visibly-degenerating neurons. These studies do not
address the long-term consequences of PHF formation; however, they
indicate that tau hyperphosphorylation, although a consequence of Aß
treatment, does not directly contribute to acute degeneration of
cultured neurons.
Pages 17-26
Erzsébet Andrásia, Éva Farkasa, Dieter Gawlikb, Ullrich Rösickb,
Peter Brätterb
Brain Iron and Zinc Contents of German Patients with Alzheimer
Disease
Abstract: Our first project aimed to determine the average
values of Fe and Zn in normal German human brain (5 individuals, 10
brain parts). Determinations were carried out by instrumental
neutron activation analysis in Berlin. Quality control measurements
were performed using National Institute of Standard Technology
standard reference materials. The present results show
non-homogeneous distribution of Fe and Zn in normal human brain. Our
second goal was to study the possible elemental concentration
changes in German patients with Alzheimer disease (5 subjects, 10
brain regions). Fe and Zn values are found to be significantly
changed in some AD brain regions compared to the controls. Another
object of this work was to extend the method for the determination
of elemental concentration not only in whole brain samples (high fat
content) but - applying two types of solvent extraction - in lipid
fraction and in brain tissue without lipid.
Pages 27-35
Sabina Capellari, Syed I. A. Zaidi, Amy C. Long, Eunice E. Kwon, and
Robert B. Petersen
The Thr183Ala Mutation, Not the Loss of the First Glycosylation
Site, Alters the Physical Properties of the Prion Protein
Abstract: The abnormal form of the prion protein has
increased resistance to protease digestion and is insoluble in
non-ionic detergents. The normal prion protein is modified by the
non-obligatory addition of two N-linked glycans. One pathogenic
mutation, Thr to Ala at residue 183 of the human prion protein,
blocks addition of the first glycan to the Asp residue 181. This
mutation has been reported to result in intracellular retention of
the mutant protein and its acquisition of pathogenic properties,
presumably due to the lack of the glycan. We report that the lack of
the N-linked glycan at residue 181 is not responsible for the block
in transport or the acquisition of pathogen-like properties, rather,
the Thr to Ala mutation is itself the probable cause of the
pathogenic phenotype.
Pages 37-46
Alafuzoff Irina, Overmyer Margit, Helisalmi Seppo, Soininen Hilkka
Lower counts of astroglia and activated microglia in patients
with Alzheimer’s disease with regular use of non-steroidal
anti-inflammatory drugs
Abstract: Epidemiological studies have indicated that
non-steroidal anti-inflammatory drugs (NSAID) may have some
therapeutic effect in Alzheimer’s disease (AD) and experimental
studies have shown that microglia activation by Aß-peptide (Aß) can
be influenced by NSAIDs. We analysed 42 clinically and
histopathologically verified demented patients fulfilling the
histopathological CERAD criteria for definite AD, representing the
terminal stage of brain degeneration. Our results indicate that
regular NSAID use has a significant influence on the load of
Ab-peptide. Furthermore, our results indicate that regular NSAID use
is associated with significantly lower counts of astrocytes and a
trend of lower counts of activated microglia in the brain tissue.
The influence of NSAID use was noted in all ApoE genotypes however
the trend of lower counts of glial cells with regular NSAID use was
more marked in patients carrying the ApoE e4/4 alleles. Based on our
results one would anticipate that regular NSAID dosing could have a
beneficial effect on the progression of the disease. However, the
fact that we failed to observe significant differences for activated
microglia might indicate an age or stage dependent difference in the
glial response i.e. in their activation rate. More studies into
age and stage related factors influencing the glial response are
required if one is to devise novel pharmacological treatment
strategies for AD.
Pages 47-57
C. Velez-Pardo, F. Lopera, M. Jimenez del Rio
DNA damage does not correlate with beta-plaques and
neurofibrillary tangles in Familial Alzheimer’s disease Presenilin-1
[E280A] mutation
Abstract: Recent studies have shown that the missense
mutation in presenilin-1 [E280A] increases deposition of amyloid-ß
(Aß[1-42/43]) producing severe cerebellar pathology. Although Aß has
been involved as a neurotoxic peptide, its role in neuronal loss in
PS-1 [E280A] patients has not yet been established. This study
investigated terminal fluorescein 12-dUTP nick-end labeling (TUNEL)-positive
cells (neuron, glia and microglial cells) and thioflavine S-stained
Aß-plaques and neurofibrillary tangles in the frontal, parietal,
temporal, occipital, hippocampus and cerebellum cortices of 3 normal
aging and 8 familial Alzheimer’s disease patients with the
presenilin-1 [E280A] mutation. Using these approaches, we found no
obvious correlation between DNA fragmentation and the severity of
amyloid-ß deposition (Aß) and neurofibrillary tangle (NFT)
formation. Indeed, we only observed 10 out of 48 FAD brain sections
displaying TUNEL (+) labeling, and none with the classical apoptotic
morphology. These results may indicate that DNA fragmentation is not
a generalized phenomenon in early-onset FAD PS1 [E280A] patients or
that neuronal cells are dying by a different mechanism of cell
death. Taking together these findings suggest that Aß and NFTs are
not per se a causative factor to damage neuronal cells but their
damage could be more related with individual neuronal vulnerability
and brain aging.
Commentaries on the Velez-Pardo
manuscript:
Pages 59-60
Akihiko Nunomura and Shigeru Chiba
Avoidance of apoptosis in Alzheimer’s disease
Pages 61-67
Paul J. Lucassen
Presenilins and cellular damage: a link through
amyloid ß
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