| Volume 6, Number 4, August
2004
Page 353
Dedicated to the Memory
of Professor Carlos Garcia - George Perry, Editor-in-Chief, JAD
Pages 355-366
Miao-Kun Sun and Daniel
L. Alkon
Cerebral Hypoperfusion and Amyloid-induced Synergistic Impairment
of Hippocampal CA1 Synaptic Efficacy and Spatial Memory in Young Adult
Rats
Abstract: Alzheimer’s disease (AD) is characterized by
amyloid plaques, neurofibrillary tangles in the brain, cerebral hypoperfusion/hypometabolism,
and amyloid angiopathy. The former two and cell loss occur late in the
disease and are probably not the leading causes for the initial memory
decline. Cerebral hypoperfusion is a pre-clinical event in AD and represents
the most accurate indicator predicting the probable AD patients to develop
AD in a future time. However, in young animals, cerebral hypoperfusion
as those matching the reduction in AD has no significant effects on learning
and memory. Here, we report that association of cerebral hypoperfusion
(2-vessel occlusion) with cerebrovascular amyloid (internal-carotid 0.5
mg Aß25-35, an active fragment of Aß) significantly impaired
spatial learning and memory of young adult rats, while neither the same
insult alone had significant impact. At the time when the spatial memory
was impaired, in vitro recording revealed that the associated cerebral
hypoperfusion and internal-carotid amyloid reduced the ability of the
hippocampal CA1 network to generate cholinergic q and the synaptic modification
evoked by associative activation of cholinergic and GABAergic inputs.
The results suggest that cerebral hypoperfusion and amyloid angiopathy
may play an important role as associated events in initiating the early
memory decline in AD.
Pages 367-377
Larry Baum, Alex Ng
Curcumin interaction with copper and iron suggests one possible
mechanism of action in Alzheimer’s disease animal models
Abstract: Curcumin is a polyphenolic diketone from turmeric. Because
of its anti-oxidant and anti-inflammatory effects, it was tested in animal
models of Alzheimer’s disease, reducing levels of amyloid and oxidized
proteins and preventing cognitive deficits. An alternative mechanism of
these effects is metal chelation, which may reduce amyloid aggregation or
oxidative neurotoxicity. Metals can induce Aß aggregation and toxicity,
and are concentrated in AD brain. Chelators desferrioxamine and clioquinol
have exhibited anti-AD effects. Using spectrophotometry, we quantified curcumin
affinity for copper, zinc, and iron ions. Zn2+ showed little binding, but
each Cu2+ or Fe2+ ion appeared to bind at least two curcumin molecules.
The interaction of curcumin with copper reached half-maximum at ~3-12 µM
copper and exhibited positive cooperativity, with Kd1~10-60 µM and
Kd2~1.3 µM (for binding of the first and second curcumin molecules,
respectively). Curcumin-iron interaction reached half-maximum at ~2.5-5
µM iron and exhibited negative cooperativity, with Kd1~0.5-1.6 µM
and Kd2~50-100 µM. Curcumin and its metabolites can attain these levels
in vivo, suggesting physiological relevance. Since curcumin more readily
binds the redox-active metals iron and copper than redox-inactive zinc,
curcumin might exert a net protective effect against Aß toxicity or
might suppress inflammatory damage by preventing metal induction of NF-kB.
Page 379-383
Venkat R. Challa, Clara R. Thore, Dixon M. Moody,
John A. Anstrom, William R. Brown
Increase of White Matter String Vessels in Alzheimer’s Disease
Abstract: String vessels are collagenous structures connected
to capillaries. They have no endothelial cells or lumen. We assessed collagen
IV-labeled string vessels in the white matter (WM) of subjects with Alzheimer’s
disease (AD) (n=12) and non-AD controls (n=11) using 100 µm celloidin
sections. Ten standard fields were digitally captured and the number and
length of normal vessels and string vessels were quantified by computerized
image analysis. The WM of the AD-diagnosed individuals contained more
strings per mm2 (3.95 ± 0.49) than comparable WM from controls
(1.36 ± 0.39) (p= 0.0005) and had increased total string vessel
length in mm/mm2 (AD = 0.29 ± 0.04; control = 0.10 ± 0.03;
p=0.0015). There was a 25% increase (not statistically significant) in
vessel density in mm/mm2 in AD subjects (AD = 11.88 ± 0.87; control
= 9.53 ± 0.78; p=0.06), presumably due to brain atrophy in the
white matter. Although vessel length was slightly increased in AD subjects,
they still had more than double the string length per total vessel length
(AD = 2.88 ± 0.38) compared to controls (1.36 ± 0.27) (p=0.0057).
This increase in string vessels in the white matter of AD subjects suggests
a decrease in vascular supply in this disease.
Pages 385-389
Domenico Praticò, Yuemang Yao, Joshua Rokach,
Martha Mayo, Gerald G. Silverberg, Dawn McGuire
Reduction of brain lipid peroxidation by CSF drainage in Alzheimer’s
disease patients
Abstract: Alzheimer’s disease (AD) is associated
with an increase in cerebrospinal fluid (CSF) levels of the isoprostane
8,12-iso-iPF2alpha-VI, a specific marker of in vivo lipid peroxidation.
Poor cerebral clearance of end products of oxidative reactions via CSF
circulation may contribute to and sustain ongoing stress. CSF drainage
via a low-flow ventriculoperitoneal (VP) shunt may improve removal of
these products, reducing oxidative stress. We quantified this biomarker
in patients with AD undergoing to VP shunt placement at baseline and after
one-year period. CSF sampling occurred at baseline and quarterly visits
for one year. Levels of this isoprostane were determined simultaneously
at the end of the study by gas chromatography negative ion chemical ionization
mass spectrometry. Over one-year, CSF 8,12-iso-iPF2a-VI levels consistently
decreased versus baseline (51% of initial level), while CSF protein, glucose,
cell count and IgG concentrations remained within normal limits. This
finding supports the hypothesis that improving CSF drainage enhances extra-cellular
clearance of end products of oxidative reactions and lowers brain lipid
peroxidation.
Pages 391-395
Wagner Malagó Tavares, Marcia Aparecida
Sperança, Roger Willian de Labio, Clovis A. Peres, Ivan Hideyo
Okamoto, Paulo Henrique Ferreira Bertolucci, Marília de A. C. Smith,
Spencer Luiz Marques Payão
ApoE 4 allele and ribosomal genes in Alzheimer's disease
Abstract: Ribosomal genes are involved in cellular transcription,
translation and gene expression modulation process. An association between
28S/18S rRNA ratio levels with apoptosis and aging has been reported.
Moulder et al. (1999) and Hashimoto et al. (2000) showed an association
between apoE 4 allele and neuronal cell apotosis through diverse mechanisms.
The apoE 4 allele is considered a late-onset Alzheimer's disease (AD)
risk factor associated with AD pathogenesis. We evaluated the association
between apoE4 allele genotyping by PCR and rRNA 28S/18S ratio by slot
blotting technique using peripheral blood samples of 18 Alzheimer's disease
patients, 18 elderly controls and 18 young controls. A rRNA ratio decrease
was observed in AD individuals confirming our previous results but this
association is independently of the ApoE4 allele genotype. Thus our results
pointed that two different mechanisms are involved in the etiology of
Alzheimer disease each one leading independently to cell death. Further
studies could investigate these factors.
Pages 397-402
Melissa Sliger, Timothy Lander, Claire Murphy
Effects of the ApoE e4 allele on Olfactory Function in Down Syndrome
Abstract: The present study investigated the effects of the apolipoprotein
E (ApoE) e4 allele, a risk factor for Alzheimer's disease (AD), on olfactory
function in Down syndrome (DS). Brain areas critical to olfactory processing,
particularly the entorhinal cortex, show the earliest neuropathological
changes in AD. Functionally, odor identification has been shown to be
impaired in AD and in persons with the e4 allele. DS is also a risk factor
for AD. Thus, we hypothesized greater impairment in e4 positive DS participants.
Olfactory function was assessed with the San Diego Odor Identification
Test in 34 participants with DS and 34 normal controls. Genomic DNA was
prepared from blood samples to obtain ApoE status for the DS participants.
Results indicate (1) that participants with DS had significant deficits
in olfactory functioning; and (2) that among DS participants, those with
an e4 allele had poorer odor identification than those without an e4 allele.
The results support the hypothesis that individuals with DS who have an
additional genetic risk factor for AD, the ApoE e4 allele, exhibit greater
deficits in odor identification. Areas of the brain involved in odor identification
may be particularly affected in individuals with DS who carry the e4 allele.
Pages 403-411
James A. Joseph, Derek R. Fisher, Amanda N. Carey
Fruit extracts antagonize Aß or DA-induced deficits in Ca2+
flux in M1-transfected COS-7 cells
Abstract: Evidence suggests that there is a selective sensitivity
to oxidative stress (OSS) among muscarinic receptor (MAChR) subtypes with
M1, M2 and M4 showing > OSS than M3 or M5 subtypes in transfected COS-7
cells. This may be important in determining the regional specificity in
neuronal aging and Alzheimer Disease (AD). We assessed the effectiveness
of blueberry (BB) and other high antioxidant (HA) fruit extracts (boysenberry,
BY; cranberry, CB; black currant, BC; strawberry, SB; dried plums, DP;
and grape, GR) on the toxic effects of Aß 25-35 (100uµM, 24
hrs) and DA (1mM, 4 hrs) on calcium buffering (Recovery) following oxotremorine
(750µM) -induced depolarization in M1AChR-transfected COS-7 cells,
and on cell viability following DA (4 hrs) exposure. The extracts showed
differential levels of Recovery protection in comparisons to the non-supplemented
controls that was dependent upon whether DA or Aß was used as the
pretreatment. Interestingly, assessments of DA-induced decrements in viability
revealed that all of the extracts had some protective effects. These findings
suggest that the putative toxic effects of Aß or DA might be reduced
by HA fruit extracts.
Pages 413-420
Yu Ping Tang, Sandra Z. Haslam, Susan E. Conrad,
Cheryl L. Sisk
Estrogen Increases Brain Expression of the mRNA Encoding Transthyretin,
an amyloid ß Scavenger Protein
Abstract: Estrogen replacement therapy in postmenopausal women
is associated with a reduced risk of Alzheimer’s Disease (AD). The
multiple mechanisms by which estrogen protects against AD are still unknown.
To conduct a broad screen for estrogen-regulated AD-related genes in the
brain, we used cDNA array assays of brain mRNA samples from ovariectomized
(ovx) adult female mice treated with either 17ß-estradiol or vehicle
at 1 or 5 weeks post-ovx. The gene encoding transthyretin (TTR), which
has been reported to scavenge amyloid ß peptides and reduce amyloid
plaque formation, is increased by estradiol treatment at both 1 and 5
weeks post-ovx. Northern blot analyses and RNase protection assays performed
on whole brain samples obtained from estradiol- or vehicle-treated mice
confirmed the cDNA array assays showing a significant increase in TTR
mRNA with estradiol treatment. Qualitative in situ hybridization or immunocytochemistry
performed on brain sections, demonstrated that TTR mRNA is expressed only
in choroid plexus and leptomeninges, and that both estrogen receptor proteins,
alpha and ß, are present in choroid plexus cells. These novel findings
suggest that estrogen may reduce the risk of AD by acting on choroid plexus
cells to increase TTR gene expression, leading to enhanced sequestration
and reduced aggregation of amyloid ß peptides.
Pages 421-431
Lopez EM, Bell KFS, Ribeiro-da-Silva A, Cuello
AC
Early changes in neurons of the hippocampus and neocortex in transgenic
rats expressing intracellular human Aß
Abstract: Alzheimer’s disease (AD) studies typically focus
on the extracellular impact of the amyloid-beta (Aß) protein, however
recent findings also implicate intracellular Aß (iAß) accumulation
in the disease’s molecular neuropathology. In a double mutant transgenic
rat model (AßPP and PS1 mutations, UKUR25), stably expressing intracellular
human Aß fragments in an environment devoid of both amyloid plaques
and neurofibrillary tangles, we investigated the impact of iAß burden
on both the incidence and relative cross sectional areas of the Golgi
apparatus, lysosomes and lipofuscin bodies. Pyramidal cells within the
hippocampus and neocortex of both transgenic and non-transgenic age matched
controls were compared. This comparison revealed a significant increase
in both the proportional area occupied by Golgi apparatus elements as
well as in the mean individual cross sectional area of Golgi compartments
in the hippocampus of transgenic rats as compared to controls. Elevated
lysosome and lipofuscin elements in the hippocampi of transgenic rats
were observed, as was an increase in the mean individual, cross sectional
area of lipofuscin bodies in the cortex of transgenic rats as compared
to controls. These findings support the hypothesis that intracellular
Aß accumulation not only has an impact on subcellular compartments
but also potentially contributes to the neuronal cell pathology observed
in AD.
Commentary on the Lopez
et al. manuscript:
Pages 433-434
Paula I. Moreira, Quan Liu, Kazuhiro Honda,
Mark A. Smith, Maria S. Santos, Catarina R. Oliveira
Is intraneuronal amyloid ß-peptide accumulation the trigger
of Alzheimer’s disease pathophysiology?
Pages 435-442
Muhammad Abdul Alim, Qiu-Lan Ma, Kazuya Takeda,
Takako Aizawa, Mamoru Matsubara, Minako Nakamura, Akiko Asada, Taro Saito,
Hiroyuki Kaji, Mitsunobu Yoshii, Shinichi Hisanaga, Kenji Uéda
Demonstration of a role for alpha-synuclein as a functional microtubule-associated
protein
Abstract: Alpha-Synuclein is a major constituent of pathological
intracellular inclusion bodies, a common feature of several neurodegenerative
diseases. Two missense mutations in the alpha-synuclein gene have been
identified in confirmed autosomal-dominant familial Parkinson's disease,
which segregate with the illness. However, the physiological function
of alpha-synuclein remains unknown. After biochemical investigations we
have revealed tubulin to be an alpha-synuclein associated/binding protein.
Here, we show that alpha-synuclein induces polymerization of purified
tubulin into microtubules. Mutant forms of alpha-synuclein lose this potential.
The binding site of alpha-synuclein to tubulin is identified, and co-localization
of alpha-synuclein with microtubules is shown in cultured cells. To our
knowledge, this is the first demonstration of microtubule-polymerizing
activity of alpha-synuclein. Now we can see a striking resemblance between
alpha-synuclein and tau: both have the same physiological function and
pathological features, making abnormal structures in diseased brains known
as synucleinopathies and tauopathies. The discovery of a physiological
role for alpha-synuclein may provide a new dimension in researches into
the mechanisms of alpha-synuclein-associated neurodegenerative diseases.
Pages 443-449
Transcript of Live Discussion held at the Alzheimer
Research Forum
Intraneuronal Aß Accumulation - More Evidence, Less Controversy?
Page 451
Book Review: Neuroscience in Medicine, Second Edition, edited by P.
Michael Conn. Humana Press, Totowa, NJ, 2003, 736 pp. Reviewed by Robert
B. Petersen.
Page 453
Book Review: The Blood-Brain Barrier, Biology & Research Protocols,
Methods in Molecular Medicine, edited by Sukriti Nag. Humana Press, Totowa,
NJ, 2003, 549 pp. Reviewed by Harry V. Vinters.
Pages 455-456
Catarina Resende Oliveira, Alexandre de Mendonça
In Memoriam: Carlos Garcia
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