| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 4, Number 1, February 2007
Contents
Editorial
Alzheimer’s Disease: Highlights from Research on Hormones,
Growth Factors and Signaling Pathways Pp. 1-2
Debomoy K. Lahiri
G Protein-Coupled Receptor Signaling Complexity
in Neuronal Tissue: Implications for Novel Therapeutics
Pp. 3-19
Stuart Maudsley, Bronwen Martin and Louis M. Luttrell
[Abstract] [Full
text article]
Glycogen Synthase Kinase-3 in Neurodegeneration and
Neuroprotection: Lessons from Lithium Pp. 21-31
Saeed Yadranji Aghdam and Steven W. Barger
[Abstract] [Full
text article]
Testosterone and Cognition in Normal Aging and Alzheimer’s
Disease: An Update Pp. 33-45
Ira Driscoll and Susan M. Resnick
[Abstract] [Full
text article]
The MT2 Melatonin Receptor Subtype is Present
in Human Retina and Decreases in Alzheimer’s Disease
Pp. 47-51
Egemen Savaskan, Ralf Jockers, Mohammed Ayoub, Debora
Angeloni, Franco Fraschini, Josef Flammer, Anne Eckert, Franz
Müller-Spahn and Peter Meyer
[Abstract] [Full
text article]
Growth and Trophic Factors and the pH, Na+/H+
Exchanger in Alzheimer´s Disease, Other Neurodegenerative
Diseases and Cancer: New Therapeutic Possibilities and Potential
Dangers Pp. 53-65
Salvador Harguindey, Stephan J. Reshkin, Gorka Orive,
Jose Luis Arranz and Eduardo Anitua
[Abstract] [Full
text article]
Increased Expression of the Remodeling- and Tumorigenic
Associated Factor Osteopontin in Pyramidal Neurons of the
Alzheimer’s Disease Brain Pp. 67-72
John K. Wung, George Perry, Aaron Kowalski, Peggy L.R.
Harris, Glenda M. Bishop, Mehul A. Trivedi, Sterling C. Johnson,
Mark A. Smith, David T. Denhardt and Craig S. Atwood
[Abstract] [Full
text article]
Oxidative Damage, Protein Synthesis, and Protein Degradation
in Alzheimer’s Disease Pp. 73-79
Qunxing Ding, Edgardo Dimayuga and Jeffrey N. Keller
[Abstract] [Full
text article]
Quetiapine to Treat Agitation in Dementia: A Randomized,
Double-Blind, Placebo-Controlled Study Pp. 81-93
Kate X. Zhong, Pierre N. Tariot, Jacobo Mintzer, Margaret
C. Minkwitz and Nancy A. Devine
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial: Alzheimer’s Disease: Highlights from Research
on Hormones, Growth Factors and Signaling Pathways
Current Alzheimer Research enters the fourth
year of successful publication with a great sense of fulfilling
our mission. During the last year, five issues of its third
volume have been completed and published on time. The third
volume featured a total of 65 articles in addition to Editorials.
These articles, comprising primary research articles and review
papers, were written and peer-reviewed by experts in neuroscience
and Alzheimer’s disease (AD). Current Alzheimer
Research remains an international journal as exemplified
by contributions from researchers belonging to 19 countries:
Australia, Austria, Belgium, Canada, China, France, Germany,
India, Israel, Italy, Japan, Netherlands, Singapore, Spain,
Sri Lanka, Taiwan, UAE, UK and the USA. Diversity of the experimental
models discussed in the last volume, which ranged from cell
culture-based to animal and human studies is also worth noting.
Success of the journal is reflected in its acceptance for
listing in Pub-Med/MEDLINE and other databases. The journal
is currently accessible via online (http://www.bentham.org/car/)
and abstracts of each article are freely available on the
journal's website.
The focus of Current Alzheimer Research continues
to be reporting mechanistic, drug-related and translational-based
advances in Alzheimer’s disease and related disorders.
A wide range of topics in AD research, including amyloid bio-genesis,
brain imaging, immunotherapy, genetics, oxidative stress and
tauopathy have been discussed by world renowned experts in
the area, and several unique and controversial topics have
been presented to encourage novel directions. In addition,
the journal continues to publish results from clinical drug
trials, including adequately-justified, evidence-based negative
data. Covering the entire AD field is not an easy task, nor
should it be our goal. For example, during the last single
year alone, AD has captured over 3,800 citations on PubMED/MEDLINE
search. Thus, the necessity of timely dissemination of this
knowledge is of great importance. Although Current Alzheimer
Research covers a small fraction of primary research,
our review articles present a comprehensive overview of selected
interesting topics, which makes an important contribution
and provide a great resource to the AD field.
In the current fourth volume, with at least 5 different issues,
Current Alzheimer Research gears up to present a
wide range of themes in the forms of critical review articles
and original research reports, which are expected to address
the neurobiology of AD, analyze potential drug targets, and
elucidate novel therapeutic strategies. The journal plans
to cover research topics in current molecular, genetic, and
in vivo models. Like previous years, the 4th
volume will occasionally bring special issues written by experts
on different “Hot Topics” of AD. Indeed, the next
issue of the journal will be a special ‘Hot Topic’
issue entitled “Exploring the Links between Obesity
and Alzheimer Research” (Guest Editor: Dr. Suzana Petanceska).
Issue 1 of the 4th volume contains 8 articles,
which address both the most interesting and relevant topics
in the field of AD and neurodegenerative disorders and the
potential utility of several valid targets for the therapy
of AD. The present issue is focused on understanding signaling
pathways, the role of different hormones and growth factors
and the relevance of each in therapeutic strategies. However,
the converging connection of these various factors to the
amyloid pathway has not been overlooked in most instances.
Several lines of evidence suggest that G protein-coupled receptors
(GPCRs) play an important role in cellular signaling. Indeed,
manipulation of transmembrane signaling by GPCRs is one of
the most important therapeutic targets although, it has not
been fully exploited in AD and other neurodegenerative diseases.
Maudsley and colleagues (page 3-19) present a timely review
on the complexity of G protein-coupled receptor signaling
in neuronal tissue and its implications for novel therapeutics.
The authors note that, with better understanding of the complexity
of GPCR signaling, the rational design of ligands possessing
increased specific efficacy and attenuated side effects should
become the norm for drug development using this important
and ubiquitous target. In the context of signaling, Aghdam
and Barger discuss (page 21-31) the potential for therapeutic
use of lithium in neuroprotective strategies and further elaborate
both the hopes and caveats of this strategy.
Elucidation of the role of different hormones in AD remains
one of the major areas of research. While effects of estrogen
on cognition and AD have been widely studied, not so much
attention has been paid to testosterone. In this context,
Driscoll and Resnick update (page 33-45) the role of testosterone
in cognition during both normal aging and AD. Particularly,
they present a succinct review of recent studies on the neurobiological
connection between testosterone and cognitive function in
humans and non-human animals. Another less-studied hormone
is melatonin. For example, it is known that the pineal hormone
melatonin regulates endogenous circadian rhythms and has various
physiological functions including neuromodulatory and vasoactive
actions, antioxidative and neuroprotective properties. However,
its role in AD has not been fully explored, although there
is recent evidence suggesting that AD patients suffer from
a disturbed pineal clock. Herein, Savaskan and investigators
suggest (page 47-51) that the MT2 melatonin receptor sub-type
is present in human retina and decreases in AD. These results
further indicate that MT2 in the humans, similarly to MT1,
may indeed be involved in transmitting melatonin’s effects
in the retina, and AD pathology may impair MT2 expression.
Apart from hormones, the role of growth and other factors
and proteins in AD is beginning to be understood. Harguindey
and collaborators present (page 53-65) an integrated approach
regarding the role of growth and trophic factors and the pH,
Na+/H+ exchanger in AD in relation to other neurodegenerative
diseases and cancer. They further discuss attendant new therapeutic
possibilities and potential dangers. In the context of novel
protein factor(s), Wung and colleagues (page 67-72) report
about Osteopontin (OPN), which is a glycophosphoprotein expressed
by several cell types and displays pro-adhesive, chemotactic,
and cytokine-like properties. This is important due to increased
expression of OPN in pyramidal neurons of the AD brain. Since
the induction of OPN expression (and amyloid-β
generation) is associated with remodeling and tumorigenesis,
the authors suggest that OPN may play a role in the aberrant
re-entry of neurons into the cell cycle and/or neuronal remyelination
in AD. But the unanswered question would be how these cellular
and bio-chemical processes become abnormal in AD pathogenesis
and in this context the next article may hold some answers.
In their review article, Ding and colleagues reinforce (page
73-79) the suggestion that protein synthesis may be one of
the earliest cellular processes disrupted by oxidative damage
in AD. Since oxidative damage selectively occurs within the
brain regions involved in regulating cognitive performance,
such studies of understanding the basis for oxidative stress
in AD have important implications in AD. Furthermore, it opens
a wide range of studies involving proteomics and proteolysis
in AD and such studies may help determine the ‘molecular
culprit’.
In addition to presenting basic research, this issue addresses
the question ‘What is the news in the drug development
area? On the clinical and drug trial front, Zhoung and colleagues
highlight (page 81-93) their studies with Quetiapine to treat
agitation in dementia. This randomized, double-blind, placebo-controlled
study suggest that Quetiapine 200mg/day is effective and well-tolerated
for treating agitation associated with dementia. However,
the investigators rightly caution about concerns regarding
increased mortality with atypical antipsychotics in this vulnerable
patient population.
In short, our major goals in the 4th volume are
to present cutting edge advances on AD from biochemical, neurobiological
and translational studies to clinical research. The ad-ditional
goal is to provide an in-depth summary of important discoveries
in AD research emphasizing those strategies on potential drug
development. The journal is also open to new ideas, hypotheses
and experimental paradigms, which will be discussed objectively
in future issues in order to enhance research and build the
road to cure this scourge.
Along with the Editorial Board and Bentham Science Publishers,
I appreciate the profound support received from the authors,
reviewers, readers, sponsors and the neuroscience community.
I sincerely hope that the journal will continue to make great
progress with all of your invaluable support and patronage.
I welcome your advice, comments and suggestions to improve
this journal. Moreover, I solicit review papers, and original
reports in various areas of AD research. This exciting journey
of knowledge about AD with your company has indeed got momentum
but destination of unlocking the mysteries of this devastating
disease is far away, and for that I need your continued support
and contributions.
Debomoy K. Lahiri
Departments of Psychiatry and of Medical and
Molecular Genetics,
Institute of Psychiatric Research,
Indiana University School of Medicine
Indianapolis, Indiana-46202
USA
[Back to top]
G Protein-Coupled Receptor Signaling Complexity
in Neuronal Tissue: Implications for Novel Therapeutics
Stuart Maudsley, Bronwen Martin and Louis M. Luttrell
[Full
text article]
The manipulation of transmembrane signaling by G protein-coupled
receptors (GPCRs) constitutes perhaps the single most important
therapeutic target in medicine. Therapeutics acting on GPCRs
have traditionally been classified as agonists, partial agonists,
or antagonists based on a two state model of receptor function
embodied in the ternary complex model. Over the past decade,
however, many lines of investigation have shown that GPCR
signaling exhibits greater diversity and ‘texture’
than previously appreciated. Signal diversity arises from
numerous factors, among them the ability of receptors to adopt
multiple ‘active’ states with different effector
coupling profiles, the formation of receptor dimers that exhibit
unique pharmacology, signaling, and trafficking, the dissociation
of receptor ‘activation’ from desensitization
and internalization, and the discovery that non-G protein
effectors mediate some aspects of GPCR signaling. At the same
time, clustering of GPCRs with their downstream effectors
in membrane microdomains, and interactions between receptors
and a plethora of multidomain scaffolding proteins and accessory/chaperone
molecules confers signal preorganization, efficiency, and
specificity. More importantly it is likely that alteration
in the interactions of these proteins with GPCRs may occur
in aging or neurodegenerative disorders, thus defining a distinct
‘pharmacology’ from that seen in young organisms
or normal physiology. In this context, the concept of agonist
selective trafficking of receptor signaling, which recognizes
that a bound ligand may select between a menu of ‘active’
receptor conformations and induce only a subset of the possible
response profile, presents the opportunity to develop drugs
that change the quality as well as the quantity of efficacy
and enhance these qualities for specific disorders or other
paradigms. As a more comprehensive understanding of the complexity
of GPCR signaling is developed, the rational design of ligands
possessing increased specific efficacy and attenuated side
effects may become the standard mode of drug development.
[Back to top]
Glycogen Synthase Kinase-3 in Neurodegeneration and
Neuroprotection: Lessons from Lithium
Saeed Yadranji Aghdam and Steven W. Barger
[Full
text article]
For over fifty years lithium has been a fundamental component
of therapy for patients with bipolar disorders. Lithium has
been considered recently for its potential to alleviate neuronal
loss and other neurodegeneration processes. For instance,
lithium reduces the severity of some behavioral complications
of Alzheimer's disease (AD). And there are growing indications
that lithium may be of benefit to the underlying pathology
of AD, as well as an array of other common CNS disorders,
including stroke, Parkinson's disease, and Huntington's disease.
Despite these demonstrated and prospective therapeutic benefits,
lithium’s mechanism of action remains elusive, and opinions
differ regarding the most relevant molecular targets. Lithium
inhibits several enzymes; significant among these are inositol
monophosphatase (IMPase), glycogen synthase kinase-3 (GSK-3),
and the proteasome. Most recent publications discussing the
medical application of lithium have converged on GSK-3, so
this article reviews data and discussions regarding the roles
and interactions of GSK-3 with other proteins and its proposed
role in the pathogenesis of Alzheimer's disease.
[Back to top]
Testosterone and Cognition in Normal Aging and Alzheimer’s
Disease: An Update
Ira Driscoll and Susan M. Resnick
[Full
text article]
There is evidence to suggest that testosterone loss constitutes
a risk for cognitive decline and possibly dementia, and that
elderly men might benefit from exogenous supplementation of
testosterone. Studies in non-human animals repeatedly report
neuroexcitatory and neuroprotective properties of testosterone
and enhanced memory performance after acute or chronic treatment.
Positive effects of testosterone supplementation in older
men have been reported in several, but not all, studies and
require replication in larger randomized clinical trials before
recommendations for clinical practice can be made. The current
review summarizes recent studies on the neurobiological connection
between testosterone and cognitive function in humans and
non-human animals. When appropriate, we use the hippocampus
as a model structure given it’s involvement in sexually
dymorphic spatial ability and sensitivity to both androgens
and aging. In addition, a number of potential explanations
of the discrepancy between data obtained in humans and non-human
animals are discussed.
[Back to top]
The MT2 Melatonin Receptor Subtype is Present
in Human Retina and Decreases in Alzheimer’s Disease
Egemen Savaskan, Ralf Jockers, Mohammed Ayoub, Debora
Angeloni, Franco Fraschini, Josef Flammer, Anne Eckert, Franz
Müller-Spahn and Peter Meyer
[Full
text article]
The pineal and retinal melatonin regulates endogenous circadian
rhythms, and has various physiological functions including
neuromodulatory and vasoactive actions, antioxidative and
neuroprotective properties. We have previously demonstrated
that the melatonin 1a-receptor (MT1) is localized
in human retinal cells and that the expression of MT1
is increased in Alzheimer’s disease (AD) patients. We
now present the first immunohistochemical evidence for the
cellular distribution of the second melatonin receptor, MT2,
in the human retina and in AD patients. In elderly controls,
MT2 was localized to ganglion and bipolar cells
in the inner nuclear layer, and to the inner segments of the
photoreceptor cells. In addition, cellular processes in inner
and outer plexiform layers were strongly positive for MT2.
In AD patients the overall intensity of MT2-staining
was distinctly decreased in all observed cellular localizations.
Our results indicate that MT2 in the humans, similar
to MT1, may indeed be involved in transmitting
melatonin’s effects in the retina, and AD pathology
may impair MT2 expression. Since our previous results
showed an increase in MT1 expression in AD retina,
the two melatonin receptor subtypes appear to be differentially
affected by the course of the neurodegenerative disorder.
[Back to top]
Growth and Trophic Factors and the pH, Na+/H+
Exchanger in Alzheimer´s Disease, Other Neurodegenerative
Diseases and Cancer: New Therapeutic Possibilities and Potential
Dangers
Salvador Harguindey, Stephan J. Reshkin, Gorka Orive,
Jose Luis Arranz and Eduardo Anitua
[Full
text article]
Abnormalities in the intricate intracellular signalling pathways
play a key role in the deregulation of either spontaneous
(normal or pathological) or induced (therapeutic) cell death
mechanisms. Some of these pathways are increasingly becoming
molecular therapeutic targets in different processes, ranging
from neurodegenerative diseases to cancer. Recent discoveries
in research and treatment have shown that failure to induce
selective cell apoptosis in hyperproliferative processes,
like neoplastic diseases, and the failure to prevent spontaneous
cell death in neurodegenerative diseases (HNDDs) such as Alzheimer's
disease (AD), multiple sclerosis (MS), amyothrophic lateral
sclerosis (ALS), Huntington´s disease (HD), and retinitis
pigmentosa (RP), can be interpreted as problems stemming from
the same basic mechanisms but moving in diametrically opposed
directions. The integrated approach advanced here represents
an interdisciplinary attempt to stimulate an integrated vision
of two otherwise widely separated areas of research, experimental
neurology and oncology. This kind of approach to the prevention
of apoptosis (therapeutic antiapoptosis) and/or other forms
of cell death in HNNDs, as well as to resistance to therapeutic
apoptosis in cancer (pathological antiapoptosis), has the
scope to improve the understanding of the dualistic nature
of the basic abnormalities underlying the pathological deregulation
of cell death. In this context, an intracellular pH (pHi)-related
approach to these opposed situations is advanced to provide
a unified theory of the apoptosis-antiapoptosis machinery.
Some potential therapeutic possibilities opened by these lines
of research, regarding the utilization of human growth factors
and/or cellular anti-acidification measures directed to sustain
cellular acid-base homeostasis in different HNNDs are considered
because of their potential therapeutic benefit. Finally, we
advance some possible dangers and side-effects raised by these
very same treatment efforts.
[Back to top]
Increased Expression of the Remodeling- and Tumorigenic
Associated Factor Osteopontin in Pyramidal Neurons of the
Alzheimer’s Disease Brain
John K. Wung, George Perry, Aaron Kowalski, Peggy L.R.
Harris, Glenda M. Bishop, Mehul A. Trivedi, Sterling C. Johnson,
Mark A. Smith, David T. Denhardt and Craig S. Atwood
[Full
text article]
Osteopontin (OPN) is a glycophosphoprotein expressed by several
cell types and has pro-adhesive, chemotactic, and cytokine-like
properties. OPN is involved in a number of physiologic and
pathologic events including angiogenesis, apoptosis, inflammation,
oxidative stress, remyelination, wound healing, bone remodeling,
cell migration and tumorigenesis. Since these functions of
OPN, and the events that it regulates, are involved with neurodegeneration,
we examined whether OPN was differentially expressed in the
hippocampus of the Alzheimer’s disease (AD) compared
with age-matched (59-93 years) control brain. We report for
the first time the immunocytochemical localization of OPN
in the cytoplasm of pyramidal neurons. In AD brains, there
was a significant 41 % increase in the expression of neuron
OPN compared with age-matched control brain. No staining of
other neuronal cell types was observed. Additionally, there
was a significant positive correlation between OPN staining
intensity and both amyloid-β
load (r2 = 0.25; P < 0.05; n = 20) and aging
(r2 = 0.32; P < 0.01; n = 20) among all control
and AD subjects. Controlling for age indicated that OPN expression
was significantly influenced by amyloid-β
load, but not age. While the functional consequences of this
amyloid-β
associated increase in OPN expression are unclear, it is notable
that OPN is primarily localized to those neurons that are
known to be vulnerable to AD-related neurite loss, degeneration
and death. Given that the induction of OPN expression (and
amyloid-β
generation) is associated with remodeling and tumorigenesis,
our results suggest that OPN may play a role in the aberrant
re-entry of neurons into the cell cycle and/or neuronal remyelination
in AD.
[Back to top]
Oxidative Damage, Protein Synthesis, and Protein Degradation
in Alzheimer’s Disease
Qunxing Ding, Edgardo Dimayuga and Jeffrey N. Keller
[Full
text article]
A large number of studies has firmly established that increases
in oxidative damage occurs in Alzheimer’s disease (AD).
Such studies have demonstrated that increased in oxidative
damage selectively occurs within the brain regions involved
in regulating cognitive performance. Studies from our laboratory
and others have provided experimental evidence that increased
levels of oxidative damage occur in subjects with Mild Cognitive
Impairment (MCI), which is believed to be one of the earliest
stages of AD, and is a condition which is devoid of dementia
or the extensive neurofibrillary pathology and neuritic plaque
deposition observed in AD. Together, these data support a
role for the accrual of oxidative damage potentially serving
as an early event that then initiates the development of cognitive
disturbances and pathological features observed in AD. Recent
studies from our laboratory have demonstrated that a decline
in protein synthesis capabilities occurs in the same brain
regions which exhibit increased levels of oxidative damage
in MCI and AD subjects. The focus of this review is to describe
the large number of studies which suggest protein synthesis
may be one of the earliest cellular processes disrupted by
oxidative damage in AD. Taken together, these findings have
important implications for understanding the molecular and
cellular basis of AD, understanding the basis for oxidative
stress in AD, and may have important implications for studies
involving proteomics and proteolysis in AD.
[Back to top]
Quetiapine to Treat Agitation in Dementia: A Randomized,
Double-Blind, Placebo-Controlled Study
Kate X. Zhong, Pierre N. Tariot, Jacobo Mintzer, Margaret
C. Minkwitz and Nancy A. Devine
[Full
text article]
In this 10-week, double-blind, fixed-dose study,
elderly institutionalized patients with dementia and agitation
were randomized (3:3:2) to quetiapine 200mg/day, 100mg/day,
or placebo. The primary endpoint was change in Positive and
Negative Syndrome Scale (PANSS)-Excitement Component (EC)
scores at endpoint, analysed using last observation carried
forward (LOCF) and observed cases (OC) approaches. Other efficacy
measures were the Clinical Global Impression of Change (CGI-C),
and response rates (percentage with =40% reduction [PANSS-EC];
“much” or “very much improved” [CGI-C]),
Neuropsychiatric Inventory-Nursing Home version (NPI-NH),
and Cohen-Mansfield Agitation Inventory (CMAI). The key safety
measure was incidence of adverse events; change in Mini-Mental
State Examination (MMSE) was also assessed. Baseline characteristics
of 333 participants (quetiapine 200mg/day, n=117; quetiapine
100mg/day, n=124; placebo, n=92) and completion rates (63-65%)
were comparable among groups. Compared with placebo, quetiapine
200mg/day was associated with clinically greater improvements
in PANSS-EC (LOCF, p=0.065; OC, p=0.014 [ANCOVA]), CGI-C (LOCF,
p=0.017; OC, p=0.002 [ANOVA]), and CGI-C response rates (LOCF,
p=0.002; OC, p<0.001 [Chi-square test]). Quetiapine 100mg/day
did not differentiate from placebo on these measures. There
were no between-group differences in NPI-NH or CMAI. Incidences
of cerebrovascular adverse events, postural hypotension, and
falls were similar among groups. MMSE did not change in any
group. Mortality was numerically higher in the quetiapine
groups; rates were not statistically different from placebo.
The results of this study suggest that quetiapine 200mg/day
was effective and well tolerated for treating agitation associated
with dementia. However, caution should be exercised given
the concerns regarding increased mortality with atypical antipsychotics
in this vulnerable patient population.
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