| Volume 2, Number
3-4, November 2000
Pages 193-198
Alan J. Lerner, Robert C. Elston, Chien Hsiun Chen, Robert P.
Friedland
Response of the hypothalamic-pituitary-adrenal axis to lumbar
puncture induced stress
Abstract: To assess lumbar puncture (LP) stress as measured
by Hypothalamic-Pituitary-Adrenal axis response, serum cortisols
were measured before and after LP in Alzheimer’s disease (AD) and
healthy elderly individuals. There were no differences in baseline
serum cortisol. AD group had significantly higher cortisols at 165
minutes post-LP. Growth curve analysis confirmed these findings and
showed significant differences in cortisol levels overall. The AD
males had higher cortisols at 105 minutes post-LP, but no other
consistent gender differences emerged. The findings are consistent
with the relative reduction in HPA negative feedback seen in AD.
Overall, LP induces little change in group mean cortisol levels
relative to inter-individual variation, indicating that while LP is
an interesting model of neuroendocrine challenge, it needs to be
tested in larger populations.
Pages 199-206
Camilla Hesse, Lars Rosengren, Eugeen Vanmechelen, Hugo
Vanderstichele, Christer Jensen, Pia Davidsson, Kaj Blennow (Communicated
by Rivka Ravid)
Cerebrospinal fluid markers for Alzheimer´s disease evaluated
after acute ischemic stroke
Abstract: Potential cerebrospinal fluid (CSF) markers for
Alzheimer´s disease (AD) include tau protein, the 42 amino-acid form
of amyloid ß (amyloid ß(1-42)) and apolipoprotein E (apoE). To study
new aspects of these protein markers, we examined consecutive CSF
samples from 26 patients with acute ischemic stroke. CSF samples
were taken on day 0-1, day 2-3, day 7-9, 3 weeks and 3-5 months
after the stroke. CSF-tau showed a marked increase day 2-3, which
peaked after 1 week and returned to normal after 3-5 months. CSF-tau
also showed correlation (r = 0,95; p<0,01) with the size of the
infarct. In contrast, CSF-amyloid ß(1-42) and CSF-apoE showed no
significant changes during the period. The marked increase in
CSF-tau levels after acute ischemic stroke indicate that CSF-tau
reflect the degree of neuronal damage. The reason for unchanged
levels of CSF-amyloid ß(1-42) and CSF-apoE after ischemic stroke
remains unclear.
Pages 207-222
Susan M. Grant, Adriana Ducatenzeiler, Moshe Szyf, A. Claudio Cuello
(Communicated by Irina Alafuzoff)
Aß immunoreactive material is present in several intracellular
compartments in transfected, neuronally differentiated, P19 cells
expressing the human amyloid ß-protein precursor
Abstract: Processing of the amyloid ß-protein precursor is
believed to play a critical role in the development of Alzheimer’s
disease neuropathology. The localization of the human Aß epitope
within mature neuroectodermally differentiated embryonal carcinoma
(P19) cells, stably transfected with the cDNA coding for a wild form
human amyloid ß-protein precursor (AßPP 751) was investigated. For
this, we applied high resolution electron microscopy and
immunocytochemistry with a newly developed, highly specfic
monoclonal antibody (McSA1). We observed immunoreactive signals in
a number of subcellular organelles such as early endosomes, the
trans-Golgi network and in the dilated rough endoplasmic reticulum,
but not in lysosomes. Occasionally Aß immunoreactivity was
associated with microtubles and filaments, with the outer
mitochondrial membrane, and with the nuclear envelope. These
observations expand on current data regarding intracellular
trafficking of AßPP fragments and provoke further questions
regarding the role of intracellular Aß peptides in basal conditions
and pathological states.
Pages 223-229
Félix F. Cruz-Sánchez, Nuria Durany, Johannes Thome, Peter Riederer
and Daniel Zambón (Communicated by Miguel Pappolla)
Correlation between apolipoprotein-E polymorphism and Alzheimer's
disease pathology
Abstract: Alzheimer's disease (AD) and small vessel disease
dementia (SVDD) are common causes of dementia. The ApoE genotype has
been proposed as a risk factor for AD. The frequency of the three
ApoE alleles was correlated with the neuropathological changes of AD
(senile plaques, neurofibrillary tangles and amyloid angiopathy) and
SVDD (status lacunaris, status cribosus, leucoencephalopathy,
micronecrosis and vascular fibrohyalinosis) in order to validate
previous ApoE genotyping results in AD and to identify pre-clinical
AD. Representative cerebral regions (cortex, gyrus cinguli, putamen,
hippocampus, white matter) from 28 AD cases, 7 SVDD and 38
non-neurological controls were studied using classical histological
techniques and immunohistochemistry for tau protein and amyloid-ß.
The frequency of the ApoE allele 4 was significantly increased not
only in AD patients but also in aged controls. However, following a
detailed histopathological examination was found 62% of this group
to exhibit histological changes associated with AD in limited brain
areas (entorhinal region, hippocampus and adjacent temporal cortex
or entorhinal region and hippocampus, or only in the entorhinal
region), but 87% of these cases were found to be ApoE4 positive. The
significant differences found in the distribution of ApoE allele
frequencies were more marked when these cases were excluded from the
control group and included as AD cases. In contrast, the frequency
of the ApoE allele 2 is significantly increased in SVDD patients.
Using histological techniques we confirmed the clinical diagnoses of
all cases and classified the AD patients according to the severity
of cortical pathology related to AD, while re-grouping from the
control group those cases which had no clinical history of the
disease but exhibited typical AD and SVDD histological lessions
which could be considered as "pre-clinical" forms of these diseases.
Pages 231-259
Marwan N. Sabbagh, Douglas Galasko, Edward Koo, Leon J. Thal
(Communicated by James Geddes)
Amyloid-ß and treatment opportunities for Alzheimer's disease
Abstract: Proposed treatments of Alzheimer's disease (AD) are
most likely to succeed if they are based on an understandng of the
complex biology of AD and its effects on cognition. Treatments may
target a single or multiple components of the complex pathology of
AD with the hope that by affecting an individual component of AD
pathology, the disease course can be affected. One such component is
amyloid-ß (Aß), a feature of the senile plaque. Aß may be critical
for inducing the pathology seen in AD. Accumulation of Aß may result
in a cascade of biochemical events leading to neuronal dysfunction,
which may present opportunities for intervention at multiple
different points to slow disease progression. Treatment may be
directed towards decreasing Aß production, increasing Aß removal,
and decreasing Aß aggregation. Alternatively, treatment may be
directed at more distal pathways by: modulating downstream events
possibly due to Aß such as free radical toxicity, decreasing
inflammation, preventing cell membrane damage, restoring calcium
homeostasis, preventing excitotoxicity, and blocking the cellular
response to injury by inhibiting neuronal apoptosis. This review
underscores the complex biology of Aß specifically looking at the
potential targets of therapeutics based on emerging knowledge of
this biology.
Pages 261-281
S. M. de la Monte, N. Ganju, N. Feroz, T. Luong, K. Banerjee, J.
Cannon, and J. R. Wands
Oxygen free radical injury is sufficient to cause some
Alzheimer-type molecular abnormalities in human CNS neuronal cells
Abstract: Cell loss and neuritic/cytoskeletal lesions
represent two of the major categories of dementia-associated
structural abnormalities in Alzheimer’s disease (AD). Cell loss is
ultimately mediated by apoptosis and mitochondrial DNA damage due to
enhanced sensitivity to oxidative stress, but the mechanism
responsible for the neuritic/cytoskeletal lesions including the
abnormal proliferation of cortical neurites is not known. This
study examines the potential role of oxygen free radical injury as a
factor contributing to both cell death and neuritic sprouting
cascades in AD. PNET2 human neuronal cells were treated with H2O2
(8 µM to 88 µM) for 24 hours and then analyzed for viability, DNA
damage, and pro-apoptosis, survival, and sprouting gene expression
and signaling. H2O2-treatment resulted in dose-dependent increases
in cell death due to genomic and mitochondrial DNA damage associated
with increased levels of 8-OHdG and the p53 and CD95 pro-apoptosis
genes, reduced levels of the Bcl-2 survival gene, activation of JNK
and p38 stress kinases, and inhibition of PI3 kinase survival
signaling. However, the H2O2-treated cells also manifested
increased expression of growth and sprouting molecules, including
GAP-43, nitric oxide synthase 3, neuronal thread protein (NTP; ~17
kD and ~21 kD forms), proliferating cell nuclear antigen, and
phospho-Erk MAPK, and normal levels of the AD-associated ~41 kD NTP
species, cyclin dependent kinase 5 (cdk-5), and phospho-tau. In
addition, the H2O2-treated cells had increased levels of p25, the
catalytically active and stable cleavage product of p35, which
regulates cdk-5 activity. Previous studies demonstrated p25
accumulation in AD brains and p25-induced hyperphosphorylation of
tau and neuronal apoptosis. The findings herein suggest that oxygen
free radical injury in human CNS neuronal cells is sufficient to
cause some but not all of the pro-death and pro-sprouting molecular
abnormalities that occur in AD.
Commentary on the de la Monte et
al. manuscript:
Pages 283-287
Craig S. Atwood
Evidence that oxidative challenges promote neuronal sprouting
and cell cycle re-entry
Pages 289-301
Brent Passer, Luca Pellegrini, Claudio Russo, Richard M. Siegel,
Michael J. Lenardo, Gennaro Schettini, Martin Bachmann, Massimo
Tabaton, Luciano D'Adamio
Generation of an apoptotic intracellular peptide by gamma-secretase
cleavage of Alzheimer's ß-amyloid precursor protein
Abstract: The amyloid ß precursor protein (AßPP) is
sequentially processed by ß- and gamma-secretases to generate the Aß
peptide. The biochemical path leading to Aß formation has been
extensively studied since extracellular aggregates of amyloidogenic
forms of Aß peptide (Aß42) are considered the culprit of Alzheimer's
disease. Aside from its pathological relevance, the biological role
of AßPP proteolysis is unknown. Although never previously
described, cleavage of AßPP by gamma-secretase should release,
together with Aß, a COOH-terminal AßPP intracellular domain, herein
termed AID. We have now identified AID-like peptides in brain
tissue of normal control and patients with sporadic Alzheimer's
disease and demonstrate that AID acts as a positive regulator of
apoptosis. Thus, overproduction of AID, may add to the toxic effect
of Aß42 aggregates and further accelerate neurodegeneration.
Pages 303-304
Book Review: Christopher M. Clark and John Q. Trojanowski
(Eds.); Neurodegenerative Dementias: Clinical Features and
Pathological Mechanisms, McGraw Hill, 2000, New York, NY, 491 pp.;
Reviewed by Colin L. Masters
Pages 305-385
Proceedings from the
First International Conference on Metals
and the Brain: From Neurochemistry to Neurodegeneration
University of Padova, Italy, 20-23 September 2000
Page 387
List of Reviewers
Page 389-392
Author Index of Volume 1
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