Volume 4, Number
6, December 2002
Pages 449-457
Justine A. Levin-Allerhand, Chris E. Lominska, Jennifer Wang,
Jonathan D. Smith (Communicated by Ralph Martins)
17alpha-estradiol and 17ß-estradiol treatments are effective in
lowering cerebral amyloid-ß levels in APPSWE transgenic mice
Abstract: Post-menopausal estrogen therapy is associated with
a decreased incidence of Alzheimer disease and in vitro
models have shown that 17ß-estradiol is effective in lowering
amyloidogenic processing. To examine the effects of estrogen
withdrawal and replacement on amyloid ß (Aß) levels and amyloid
ß-protein precursor (AßPP) processing in vivo, Swedish mutant
AßPP transgenic mice were ovariectomized or sham ovariectomized at
four weeks of age and treated with placebo or 17ß- or
17alpha-estradiol pellets, the latter being a weak estrogen receptor
agonist. Compared to sham ovariectomized mice, ovariectomy with
placebo did not alter Aß levels; however, the levels of Aß were
decreased by 27% and 38% in mice treated with 17ß- and
17alpha-estradiol, respectively, with no change in AßPP holoprotein.
Endogenous and exogenous estrogen both significantly increased the
levels of sAPPalpha, the secreted form of AßPP. The ratio of Aß/sAPPalpha,
a measure of amyloidogenic processing, was reduced in all
estrogen-containing groups. The Aß lowering effect of 17ß- and
17alpha-estradiol was replicated when estrogens were administered at
a more physiological dose in the drinking water, or when mice were
ovariectomized at three months of age. The increased efficacy of
17alpha-estradiol versus 17ß-estradiol may help to develop safe and
effective therapeutics.
Pages 459-466
Pamela Zambenedetti, Horst P. Schmitt, Paolo Zatta
Metallothionein I-II immunohistochemical reactivity in
Binswanger’s encephalopathy
Abstract: Binswanger’s disease is a subacute form of
hypertensive encephalopathy characterized by patchy-confluent myelin
loss of the deep hemispheric white matter, associated with marked
regressive changes of the oligodendrocytes and variable astroglial
reaction. To understand the distribution and the specificity of
astrocyte pathology in Binswanger’s disease we quantified reactive
and degenerating astrocytes in different regions of the deep and
subcortical white matter and of the cerebral cortex. Sections of
frontal, temporal, parietal, and occipital lobes of 12
histologically proven cases of Binswanger’s disease were
immunostained with antibodies to glial fibrillary protein (GFAP) and
to metallothionein I and II (MT-I-II), markers which specifically
identify normal and reactive astrocytes. Control tissues were from 6
elderly patients without neurological diseases. The brains of
Binswanger’s disease were characterized by few and lightly
immunostained astrocytes in the deep white matter, but normal and
reactive astrocytes, strongly immunoreactive for GFAP and MT-I-II,
were prominent in the subcortical white matter and the cerebral
cortex. However, the relative distribution of GFAP positive and
MT-I-II positive astrocytes was significantly different between the
cerebral cortex and the subcortical white matter, the MT-I-II
positive astrocytes being more frequent in the cerebral cortex, and
the GFAP positive astrocytes in the subcortical white matter
(p<0.02). The GFAP and MT-I-II expressions in subsets of reactive
astrocytes in the cortico-subcortical layers together with
regressive astroglial changes in the deep white matter suggest that
the dynamic plasticity of astroglia is topographically and
biochemically differentiated in vascular dementia of Binswanger
type.
Pages 467-478
Zeinab Khalil, Helen Poliviou, Christa J Maynard, Konrad Beyreuther,
Colin L. Masters, Qiao-Xin Li
Mechanisms of peripheral microvascular dysfunction in transgenic
mice overexpressing the Alzheimer's disease amyloid Aß protein
Abstract: Freshly prepared soluble amyloid ß (Aß) peptide has
been reported to have vascular actions both in vitro and
in vivo. This study was designed to examine the in vivo
microvascular effects of Aß in two skin microvascular model systems
that might reflect possible short and long-term vascular effects of
this peptide. Short-term vascular effects were examined using
freshly prepared soluble Aß(1-40) peptide superfused over naive rat
skin microvasculature for 15 min. Peripheral microvascular
functional changes in 9-months-old transgenic (Tg) mice
overexpressing soluble Aß in the brain, peripheral circulation and
other tissues, were also examined. Microvascular responses were
monitored using laser Doppler flowmetry from the base of a blister
raised on the hind footpad of the animals. Endothelial-dependent and
independent vasodilatation responses (VD) were examined using
acetylcholine (ACh) and sodium nitroprusside (SNP) respectively. The
exposure of naïve rat microvasculature to Aß1-40) resulted in an
immediate vasoconstriction (VC) that prevented ACh but not SNP from
inducing a subsequent VD response. The vascular effects of Aß(1-40)
were reversed by antioxidants (superoxide dismutase and catalase)
and an endothelin A (ETA) receptor antagonist (BQ-123). Tg mice
overexpressing soluble Aß and C100 showed significant reductions in
both endothelial-dependent and endothelial-independent VD that were
also reversed by antioxidants and BQ-123. In conclusion, this study
provided evidence to support the notion of peripheral vascular
effects of Aß in vivo and present novel evidence for
alterations in endothelial and smooth muscle cell function in
peripheral skin microvasculature in Tg mice overexpressing Aß and
C100. We suggest that skin microvasculature is a useful model to
examine the mechanisms underlying the vascular actions of the Aß
protein.
Pages 479-486
Peter Bozner, G. Lee Wilson, Nadya M. Druzhyna, Tara K.
Bryant-Thomas, Susan P. LeDoux, Glenn L. Wilson, Miguel A. Pappolla
Deficiency of chaperonin 60 in Down's syndrome
Abstract: Patients with Down syndrome (DS) and Alzheimer's
disease (AD) share a number of characteristic neuropathologic
lesions. Several lines of evidence suggest that mitochondria and
the oxidative stress response are involved in the pathogenesis of
both conditions. In the process of investigating the stress
response in DS, we discovered a defective basal expression of a
major mitochondrial heat shock protein, chaperonin 60 (Cpn60) in
non-transformed dermal fibroblast cell lines from DS individuals.
Such a defect was not present in control cells that had been
cultured under identical physiological growth conditions. A
quantitative analysis by Western blots showed a marked reduction of
Cpn60 per equal amount of total protein in DS cells to an average of
35% of normal. Northern blot studies confirmed the defect and also
showed a marked reduction of the mRNA signal for Cpn60 in all the DS
cell lines. To gain further information, experiments were conducted
to study the rate of de-novo synthesis of Cpn60 at normal and
supraoptimal temperatures in DS and controls. Results showed no
significant differences between the two study groups. HSP60 is
important in mitochondrial function and defects in these organelles
have been reported in DS and AD. Thus, the findings may have
potential implications in the neuropathology of DS.
Pages 487-496
TracyAnn Perry, Nigel H. Greig
The glucagon-like peptides: a new genre in therapeutic targets
for intervention in Alzheimer’s disease
Abstract: Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an
insulinotropic hormone, secreted from the enteroendocrine L cells of
the intestinal tract in response to nutrient ingestion. It enhances
pancreatic islet ß-cell proliferation and glucose-dependent insulin
secretion, and lowers blood glucose in patients with type 2 diabetes
mellitus. GLP-1 receptors, which are coupled to the cyclic AMP
second messenger pathway, are expressed throughout the brains of
rodents and humans. The chemoarchitecture of receptor distribution
in the brain correlates well with a central role for GLP-1 in the
regulation of food intake and response to aversive stress. We have
recently reported that GLP-1 and several longer acting analogs that
bind at the GLP-1 receptor, possess neurotrophic properties, and
offer protection against glutamate-induced apoptosis and oxidative
injury in cultured neuronal cells. Furthermore, GLP-1 can modify
processing of the amyloid ß-protein precursor in cell culture and
dose-dependently reduces amyloid ß-peptide levels in the brain in
vivo. As such, this review discusses the known role of GLP-1
within the central nervous system, and considers the potential of
GLP-1 and analogs as novel therapeutic targets for intervention in
Alzheimer’s disease (AD) and potentially other central and
peripheral neurodegenerative conditions.
Pages 497-512
Jack C. de la Torre
Alzheimer’s disease: how does it start?
Abstract: Presently, non-genetic Alzheimer’s disease (AD) is
wrongly classified as a neurodegenerative disorder. When vascular
lesions are present, AD is considered to be a vascular dementia.
However, compelling evidence indicates that AD is a vascular
disorder with neurodegenerative consequences. There is an urgent
clinical need to ascertain the true cause of this dementia. In this
review, evidence indicating that AD is a vascular disorder comes
from a number of different disciplines including studies in
epidemiology, pharmacology, neuroimaging, clinical medicine,
pathology, physiology and experimental research. This collective
evidence also addresses many previously puzzling questions
regarding: i) past and present treatment failures in AD, ii) strange
association of AD risk factors with many vascular-related disorders,
iii) parallel lesions, clinical symptoms risk factors and
potentially interchangeable treatments present in AD and vascular
dementia, iv) historical difficulty in finding neurodegenerative
markers to detect AD pre-clinivally, and, v) paradoxical
pathophysiologic events preceding AD neurodegenerative changes.
Re-classifying AD as a vascular disorder would very likely improve
the chances of finding a useful treatment for this disorder because
clinical study designs could focus on more realistic and relevant
pathologic targets than is presently practiced. A short summary of
potential new research lines that may provide novel therapy in the
treatment and management of AD is discussed.
Commentary on the de la Torre
manuscript:
Pages 513-516
Gjumrakch Aliev
Is Non-Genetic Alzheimer’s Disease a Vascular Disorder with
Neurodegenerative Consequences?
Pages 517-522
M. Cristina Polidori, Patrizia Mecocci
Plasma susceptibility to free radical-induced antioxidant
consumption and lipid peroxidation is increased in very old subjects
with Alzheimer disease
Abstract: Oxidative stress is believed to play a major role
in the pathogenesis of Alzheimer disease (AD). Plasma concentrations
of vitamins C, A and E, of uric acid, thiols and carotenoids were
lower and of malondialdehyde (MDA) higher in 35 AD patients (85.9 ±
5.5 y) compared to 40 controls (85.5 ± 4.4 y) . Differences were
significant for vitamin C, vitamin E, lutein, lycopene, a-carotene
and MDA (p < 0.001). Plasma exposed to peroxyl radicals showed a
rate of antioxidant consumption and of MDA production higher in AD
patients than in controls. AD in advanced age is accompanied by a
poor plasma antioxidant status and increased plasma lipid
peroxidation, as well as by a low resistance to peroxyl radical
exposure.
Pages 523-529
D. Larry Sparks, Jeff Lochhead, Donna Horstman, Tom Wagoner, Tim
Martin
Water quality has a pronounced effect on cholesterol-induced
accumulation of Alzheimer amyloid ß (Aß) in rabbit brain
Abstract: Increased circulating cholesterol is known to
promote risk of coronary artery disease. It is now emerging that
cholesterol promotes production and accumulation of amyloid ß (Aß)
deposited in the hallmark pathologic lesion of Alzheimer’s disease
(AD), the senile plaque, perhaps by shifting away from normal
metabolism of amyloid ß protein precursor (AßPP) to Aß. Previous
studies employing the cholesterol-fed rabbit model of AD
demonstrated that induction of AD-like Aß accumulation in brain
could be reversed by co-administration of cholesterol lowering drugs
or removing cholesterol, prompted initiation of an AD
Cholesterol-Lowering (Statin) Treatment Trial. We now present data
that identify a previously unrecognized role for dietary water
quality on the severity of neuropathology induced by elevated
cholesterol. Neuronal accumulation of Aß induced by increased
circulating concentrations of cholesterol in the New Zealand white
rabbit is attenuated when distilled drinking water is administered
compared to use of tap water. The numbers of neurons in
cholesterol-fed rabbits that exhibited Aß immunoreactivity, relative
to normal chow-fed controls, increased ~2.5 fold among animals on
tap water but only ~1.9 fold among animals on distilled water. This
yielded a statistically significant ~28% reduction due to the use of
distilled water. In addition, the subjectively assessed intensity
of neuronal Aß immunoreactivity was consistently reduced among
cholesterol-fed rabbits allowed distilled drinking water compared to
cholesterol-fed rabbits on tap water. As intensity of antibody
immunoreactivity is likely related to concentration of antigen, the
identified difference among cholesterol-fed rabbits allowed
distilled drinking water may hold greater importance than a
significant reduction in numbers of affected neurons. The effect
on neuronal Aß immunoreactivity intensity was observable among
cholesterol-fed rabbits reared and allowed tap water when performing
studies in three distinct locales. Pilot data suggest the
possibility of increased clearance of Aß from the brain, identified
as increased blood levels, among cholesterol-fed rabbits
administered distilled water compared to animals on tap water. The
agent(s) occurring in tap water, excluded by distillation, promoting
accumulation of neuronal Aß immunoreactivity is(are) yet
undisclosed, but arsenic, manganese, aluminum, zinc, mercury, iron
and nitrate have tentatively been excluded because they were not
identifiable (below detection limits) in the tap water of the three
locales where the cholesterol-induced neuropathologic difference was
observable. These findings suggest that water quality may impact on
human health in the setting of increased circulating cholesterol
levels, and could illustrate a truly simple life-style change that
could be of benefit in AD.
Pages 531-537
Sharon Moalem, Maire E. Percy
Hypothesis: The Quandary of Reductionism: Relevance to Alzheimer
Disease Research
Abstract: Modern science has embraced reductionism, seeking
ever-smaller parts to explain the whole. Although reductionistic
approaches are successful in very simple biological modelling, they
are not necessarily appropriate for systems of increasing
complexity. Drawing on famous historical examples of how non-reductionist
thinking has benefited mankind, and of how reductionism has
sometimes led to erroneous conclusions, we call attention to the
need to move away from purely linear reasoning in order to succeed
in addressing many of the problems we face with the predicted
demographic increase in seniors, and the increase in numbers of
those afflicted with Alzheimer disease. The time has come to
reconsider and seriously question our most basic assumptions and
beliefs surrounding what we believe Alzheimer disease to be, without
which we run the risk of missed opportunities and failure.
Page 539
List of Reviewers
Pages 541-544
Author Index of Volume 3
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