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Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 8, Number 2, March 2011
Contents
Hot Topic
Pro-Inflammatory Processes in the Alzheimer's
Pathology
Guest Editor: A. Claudio Cuello
Editorial:
Pro-Inflammatory Processes in the Alzheimer's Pathology
Pp. 114
A.C. Cuello
Molecular Mechanisms and Therapeutic Application
of NSAIDs and Derived Compounds in Alzheimer`s Disease
Pp. 115-131
M.T. Heneka, M.P. Kummer, S. Weggen, B. Bulic, G. Multhaup,
L. Münter, M. Hüll, T. Pflanzner and C.U.
Pietrzik
[Abstract] [Purchase
Article]
Inflammatory Risk Factors and Pathologies Associated
with Alzheimer’s Disease Pp. 132-141
M. Sastre, J.C. Richardson, S.M. Gentleman and
D.J. Brooks
[Abstract] [Purchase
Article]
The Early Involvement of the Innate Immunity in the
Pathogenesis of Late on Set Alzheimer’s Disease: Neuropathological,
Epidemiological and Genetic Evidence Pp. 142-150
P. Eikelenboom, R. Veerhuis, E. van Exel, J.J.M.
Hoozemans, A.J.M. Rozemuller and W.A. van Gool
[Abstract] [Purchase
Article]
The Role of Microglial Cell Subsets in Alzheimer’s
Disease Pp. 151-155
G. Naert and S. Rivest
[Abstract] [Purchase
Article]
How to Get from Here to There: Macrophage Recruitment
in Alzheimer’s Disease Pp. 156-163
K. Rezai-Zadeh, D. Gate, G. Gowing and T. Town
[Abstract] [Purchase
Article]
Does a Pro-Inflammatory Process Precede Alzheimer’s
Disease and Mild Cognitive Impairment? Pp. 164-174
M.T. Ferretti and A.C. Cuello
[Abstract] [Purchase
Article]
General Articles
Long-Term Response to Galantamine in Relation
to Short-Term Efficacy Data: Pooled Analysis in Patients with
Mild to Moderate Alzheimer’s Disease Pp. 175-186
S. Kavanagh, I. Howe, H.R. Brashear, D. Wang, B. Van Baelen,
M. Todd and S. Schwalen
[Abstract] [Full
Text Article]
Apo-Eε4
Allele in Conjunction with Aβ42
and Tau in CSF: Biomarker for Alzheimer’s Disease Pp.
187-196
R.J.L. Kandimalla, S. Prabhakar, B.K. Binukumar,
W.Y. Wani, N. Gupta, D.R. Sharma, A. Sunkaria, V.K. Grover,
N. Bhardwaj, K. Jain and K.D. Gill
[Abstract] [Purchase
Article]
Correlation Analysis of Capillary APOE, VEGF and eNOS
Expression in Alzheimer Brains Pp. 197-202
J. Provias and B. Jeynes
[Abstract] [Purchase
Article]
EHT0202 in Alzheimer’s Disease: A 3-Month, Randomized,
Placebo-Controlled, Double-Blind Study Pp. 203-212
B. Vellas, O. Sol, P.J. Snyder, P.-J. Ousset,
R. Haddad, M. Maurin, J.-C. Lemarié, L. Désiré,
M.P. Pando and on behalf of EHT0202/002 study group
[Abstract] [Purchase
Article]
Neuronal Membranes are Key to the Pathogenesis of
Alzheimer’s Disease: the Role of Both Raft and Non-Raft
Membrane Domains Pp. 213-221
R. Williamson and C. Sutherland
[Abstract] [Purchase
Article]
Abstracts
[Back to top]
Editorial:
Pro-Inflammatory Processes in the Alzheimer's Pathology
A.C. Cuello
The role of inflammatory processes in Alzheimer's disease
(AD) represents an area of great significance to the field
of clinical research; however, the relevance of inflammatory
response remains intensively debated. Early epidemiological
studies have demonstrated quite convincingly that the prolonged
use of NSAIDs consistently diminishes the incidence of AD.
As a result, these clinical observations greatly enhanced
interest in NSAIDs, and spurred efforts to elucidate the inflammatory
and immunological mechanisms involved in the neuropathology
of AD. Most importantly, these findings led to a number of
prospective clinical trials using NSAIDS and other anti-inflammatory
reagents. However, these trials yielded largely disappointing
results. These negative findings could signify that we have
not found the right biological target. Additionally, after
the clinical diagnosis of AD, it may simply be too late to
delay or reverse AD pathology with therapeutic intervention
using NSAIDs. In either case, in-depth knowledge of the inflammatory
and immunological processes which aggravate or ameliorate
the neuropathology of AD is likely fundamental to establish
future therapeutic opportunities. Current research efforts
are rapidly gaining insight into the possible preclinical
benefits of NSAIDs.
This Hot Topics issue of Current Alzheimer's Research intends
to review many of the fundamental problems relating inflammatory
processes with the Alzheimer's neuropathology. The individual
contributions collated here thoroughly review the literature
and address the most urgent questions by discussing observations
made in molecular-cell systems, transgenic models and human
post-mortem brain material, and relate these findings to the
lessons derived from recent clinical trials. In closing I
would like to thank Professor Debomoy K. Lahiri, the Editor
in Chief of Current Alzheimer's Research for so positively
responding to my suggestion of a special issue on: "Pro-inflammatory
processes in the Alzheimer’s Pathology". I am also
gratified by the enthusiastic response and excellent contributions
received for this issue. Special thanks are due to Piet Eikelenboom,
Michael Heneka, Magdalena Sastre, Serge Rivest, Terrence Town
and their excellent collaborators. I trust their articles
will be valuable to many researchers in the field of AD.
On a personal note, I profoundly enjoyed this experience in
that I now know some very interesting colleagues whom I had
known previously only by their publications. Finally, special
thanks are due to my assistant, Maureen Driscoll, who was
of invaluable help in collating materials and their editing,
and incredible support from the staff of Current Alzheimer
Research of Bentham.
A. Claudio Cuello
Guest Editor
Current Alzheimer Research
Professor and Charles E. Frosst Merck
Chair in Pharmacology
Department of Pharmacology and Therapeutics
McGill University, 3655 Promenade Sir-William-Osler
Room 1325, Montreal, Quebec
Canada, H3G 1Y6
Tel: 514-398-3618;
Fax: 514-398-8317
E-mail: claudio.cuello@mcgill.ca
[Back to top] [Purchase
Article]
Molecular Mechanisms and Therapeutic Application
of NSAIDs and Derived Compounds in Alzheimer`s Disease
M.T. Heneka, M.P. Kummer, S. Weggen, B. Bulic, G. Multhaup,
L. Münter, M. Hüll, T. Pflanzner and C.U.
Pietrzik
Alzheimer’s disease (AD) is the most common form
of neurodegenerative dementias worldwide. Amyloid-β
deposition, neurofibrillary tangle formation and Neuroinflammation
are the major pathogenetic mechanisms that in concert lead
to memory dysfunction and decline of cognition. To date, there
is no curative treatment for AD. Epidemiological analysis
support the notion that sustained intake of non-steroidal
anti-inflammatory drugs (NSAIDs) reduce the risk and delay
the onset of AD. In contrast, therapeutic studies testing
NSAID efficacy in AD patients have not yielded positive results.
This suggests that either the investigated drugs have not
addressed the mechanism of action required for mediating beneficial
effects or that NSAIDs are effective at stages way before
clinical onset of symptoms. The NSAIDs concerned are pleiotrophic
in nature and interact with more than one pathomechanism.
Therefore evidence for more than one neuroprotective action
of NSAIDs has been put forward and it seems likely that some
of the drugs act at multiple levels through more than one
molecular mechanism. Some, even may not only be beneficial,
but negative actions may be overruled by protective effects.
Within these mechanisms, modulation of
γ-secretase activity, the activation of the peroxisome
proliferator- activated receptor-γ,
binding to prostaglandin receptors or interactions at the
blood-brain barrier may account for the observed protection
from AD. This article reviews the current knowledge and views
on the above mechanisms and critically discusses current obstacles
and the potential as future AD therapeutics.
[Back to top] [Purchase
Article]
Inflammatory Risk Factors and Pathologies Associated
with Alzheimer’s Disease
M. Sastre, J.C. Richardson, S.M. Gentleman and
D.J. Brooks
The importance of inflammatory processes in Alzheimer’s
disease (AD) progression has been confirmed during the past
decade by the intensive investigation of inflammatory mediators
in the brain of AD patients as well as by the genetic and
drug manipulation of animal models of AD. Imaging studies
have revealed that the activation of microglia occurs in early
stages of the disease, even before plaque and tangle formation,
and is correlated with early cognitive deficits. In this review,
we analyze how different risk factors, such as trauma, stroke,
infection, and metabolic diseases can lead to an acceleration
of the inflammatory response in the AD brain and to an increased
risk of developing this disorder. The use of imaging techniques
for early detection of glial activation which offer the advantage
of investigating how potential antiinflammatory therapies
may influence disease progression and levels of cognition
is also discussed.
[Back to top] [Purchase
Article]
The Early Involvement of the Innate Immunity in
the Pathogenesis of Late on Set Alzheimer’s Disease:
Neuropathological, Epidemiological and Genetic Evidence
P. Eikelenboom, R. Veerhuis, E. van Exel, J.J.M.
Hoozemans, A.J.M. Rozemuller and W.A. van Gool
The idea that an inflammatory process is involved in Alzheimer’s
disease (AD) was proposed already hundred years ago but only
the past twenty years inflammation-related proteins have been
identified within plaques. A number of acute-phase proteins
colocalize with the extracellular amyloid fibrils, the so
called Aβ-associated
proteins. Activated microglia and astrocytes surrounding amyloid
deposits express receptors of innate immunity and secrete
pro-inflammatory cytokines. In this paper we review the evidence
for involvement of innate immunity in the early stages of
the pathological cascade of AD. Diffuse plaques, the initial
neuropathological lesion in the cerebral neocortex, contain
next to Aβ
also apolipoprotein E, clusterin, 1-antichymotrypsin and activated
complement proteins. Interestingly, genetic studies have shown
gene-loci to be associated with AD for all these proteins,
except 1-antichymotrpsin. Fibrillar Aβ
can, through stimulation of toll-like receptors and CD-14
on glial cells, activate pathways for increased production
of pro-inflammatory cytokines. This pathway, inducing production
of proinflammatory cytokines, is under genetic control. The
finding that the responsiveness of the innate immunity is
higher in offspring with a parental history of late-onset
AD indicates heritable traits for AD that are related to inflammatory
processes. Prospective epidemiological studies which report
that higher serum levels of certain acute-phase proteins are
associated with cognitive decline or dementia provide additional
evidence for the early involvement of inflammation in AD pathogenesis.
The reviewed neuropathological, epidemiological and genetic
findings show evidence for involvement of the innate-immunity
in the early stages of pathological cascade as well as for
the hypothesis that the innate immunity contributes to the
etiology of late-onset AD.
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Article]
The Role of Microglial Cell Subsets in Alzheimer’s
Disease
G. Naert and S. Rivest
Alzheimer disease (AD) is characterized by a progressive
cognitive decline and accumulation of β-amyloid
(Aβ)
forming senile plaques that are associated with inflammatory
molecules and cells. Resident microglia and newly differentiated
cells that are derived from the bone marrow are found in the
vicinity of Aβ
plaques. Although these two types of microglia are not distinguishable
by specific markers in the brain, they seem to possess different
phenotype and functions. In mouse models of AD, bone marrow-derived
microglia (BMDM) have been shown to delay or stop the progression
of AD and preventing their recruitment exacerbates the pathology.
Transplantation of competent hematopoietic stem cells or their
genetic modifications ameliorate cognitive functions, reduce
Aβ
accumulation and prevent synaptic dysfunctions. Improving
the recruitment of genetically-modified BMDM may be considered
as a powerful new therapeutic strategy to counteract AD. Here
we review the role of microglia subsets in AD and how these
cells have a great potential to fight against Aβ
accumulation and cognitive impairment.
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Article]
How to Get from Here to There: Macrophage Recruitment
in Alzheimer’s Disease
K. Rezai-Zadeh, D. Gate, G. Gowing and T. Town
Alzheimer’s disease (AD) is pathologically defined
by presence of intracellular neurofibrillary tangles and extracellular
amyloid plaques comprised of amyoid-β
(Aβ)
peptides. Despite local recruitment of brain microglia to
sites of amyloid deposition, these mononuclear phagocytes
ultimately fail at restricting β-amyloid
plaque formation. On the other hand, it is becoming increasingly
clear that professional phagocytes from the periphery possess
Aβ
clearance aptitude. Yet, in order to harness this beneficial
innate immune response, effective strategies must be developed
to coax monocytes/macrophages from the periphery into the
brain. It has previously been suggested that Aβ
‘immunotherapy’ clears cerebral Aβ
deposits via mononuclear phagocytes, and recent evidence suggests
that targeting transforming growth factor-β-Smad
2/3 signaling and chemokine pathways such as Ccr2 impacts
blood-to-brain trafficking of these cells in transgenic mouse
models of AD. It has also been shown that the fractalkine
receptor (Cx3cr1) pathway plays a critical role in chemotaxis
of mononuclear phagocytes toward neurons destined for death
in AD model mice. In order to translate these basic science
findings into AD treatments, a key challenge will be to develop
a new generation of pharmacotherapeutics that safely and effectively
promote recruitment of peripheral amyloid phagocytes into
the AD brain.
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Article]
Does a Pro-Inflammatory Process Precede Alzheimer’s
Disease and Mild Cognitive Impairment?
M.T. Ferretti and A.C. Cuello
The occurrence of a plaque-dependent inflammation in Alzheimer’s
disease has been extensively documented in both human specimens
and transgenic models of the disease. Since insoluble plaques
are present in AD patients from early preclinical stages of
the pathology, the point at which neuroinflammation first
occurs in the progression of the AD pathology is still unknown.
In this review we discuss the clinical and experimental evidence
for the occurrence of inflammation in preclinical, asymptomatic
phases of the progression of the AD pathology. In particular,
we discuss the evidence from different transgenic models suggesting
that a pro-inflammatory process might even be initiated prior
to plaque deposition. The factors responsible for the early,
pre-plaque inflammation are reviewed, with particular emphasis
on the role of soluble Aβ-oligomers.
Furthermore, we analyze the consequences of the microglial
activation and the deregulation of NGF metabolism, in the
context of the earliest amyloid pathology. Finally, we propose
MMP-9 as a promising biomarker for signalling early stages
of an ongoing CNS inflammation.
[Back to top]
[Full Text Article]
Long-Term Response to Galantamine in Relation to Short-Term
Efficacy Data: Pooled Analysis in Patients with Mild to Moderate
Alzheimer’s Disease
S. Kavanagh, I. Howe, H.R. Brashear, D. Wang, B. Van Baelen,
M. Todd and S. Schwalen
Background: This analysis aimed to identify
an operational, clinically relevant definition of response
achieved in short-term clinical trials to support the identification
of patients with Alzheimer’s disease (AD) who would
benefit most from long-term galantamine therapy.
Methods: Data were analyzed from 6 randomized placebo-controlled
trials of up to 6 months’ duration, which included patients
with mild to moderate AD receiving maintenance doses of galantamine
16-24 mg/day, and from 12 open-label extensions (galantamine
24 mg/day maintenance therapy). Assessments included changes
from baseline in the 11-item AD Assessment Scale-Cognitive
subscale (ADAS-Cog 11).
Results: Pooled analysis of the 5- 6 month trial
data showed that at the trial endpoint (2-5 months after reaching
maintenance doses), the proportions of galantamine- (n=1,173)
versus placebo-treated patients (n=801) with probable AD categorized
according to “improved”, “stable”
or “non-rapid decline” criteria, were 45.8% versus
27.2%, 59.5% versus 37.1%, and 87.6% versus 69.7%, respectively
(observed cases analysis), whilst changes in ADAS-Cog 11 scores
versus baseline were -4.9, -4.7 and -2.9 points, respectively,
for “improved”, “stable” and “non-rapid
decline” galantamine-treated patients (-1.5 points for
galantamine recipients overall). “Improved” or
“stable” galantamine-treated patients displayed
mean improvement in ADAS-Cog 11 scores over baseline until
18 months after starting treatment, and attenuated deterioration
thereafter; for galantaminetreated patients exhibiting “non-rapid
decline”, mean ADAS-Cog 11 score returned to baseline
after approximately 12 months.
Conclusions: Patients who demonstrate improvement,
stability, or limited cognitive decline 2-5 months after reaching
maintenance doses of galantamine are more likely to experience
continued benefit from long-term galantamine therapy.
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Article]
Apo-Eε4
Allele in Conjunction with Aβ42
and Tau in CSF: Biomarker for Alzheimer’s Disease
R.J.L. Kandimalla, S. Prabhakar, B.K. Binukumar,
W.Y. Wani, N. Gupta, D.R. Sharma, A. Sunkaria, V.K. Grover,
N. Bhardwaj, K. Jain and K.D. Gill
The objective of this study was to elucidate an association
between Apo- Eε4
allele and CSF biomarkers Aβ42
and tau for the diagnosis of Alzheimer’s Disease (AD)
patients. Aβ42 and tau protein concentrations in CSF
were measured by using ELISA assays. The levels of Aβ42
were found to be decreased where as tau levels increased in
AD patients. Moreover in AD patients Apo-Eε4
allele carriers have shown low Aβ42
levels (328.86 ±
99.0 pg/ml) compared to Apo-Eε4
allele non-carriers (367.52 ±
57.37 pg/ml), while tau levels were higher in Apo-Eε4
allele carriers (511 ±
44.67 pg/ml) compared to Apo-Eε4
allele non-carriers (503.75 ±
41.08 pg/ml). Combination of Aβ42
and tau resulted in sensitivity of 75.38% and specificity
of 94.82% and diagnostic accuracy of 84.30% for AD compared
with the controls. Therefore low Aβ42
and elevated tau concentrations in CSF may prove to be a better
diagnostic marker for AD along with the Apo-Eε4
allele.
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Correlation Analysis of Capillary APOE, VEGF and
eNOS Expression in Alzheimer Brains
J. Provias and B. Jeynes
Vasoactive regulatory and transport proteins can modify
the transendothelial blood-brain barrier (BBB) transport of
beta-amyloid. Dysfunction of one or more of these proteins
is hypothesized to contribute to the pathogenesis of Alzheimer’s
disease (AD). In this study we investigated superior temporal
and occipital cortical sections from ten AD and ten control
group brains (CG). They were examined using immunohistochemical
techniques staining for β42
amyloid, APOE, VEGF and eNOS. The densities of senile plaques
(SPs) and APOE, VEGF and eNOS positive capillaries in each
region and in each AD and CG condition were compared using
nonparametric statistical analysis. In the AD cases, there
were significant negative correlations between APOE
positive capillaries and β42
amyloid SPs, and positive correlations between APOE
positive capillaries and VEGF and eNOS positive capillaries.
These results demonstrate the increased presence
of APOE activity in AD brain capillaries, and that there is
a positive correlation between the expression of APOE and
each of VEGF and eNOS in the capillaries of AD brains. It
is possible, therefore, that the down regulation of APOE in
AD brains may contribute significantly to the pathogenesis
of SP lesion development by modulating brain β-amyloid
burden. The specific interrelationship between APOE, VEGF
and eNOS activity at the BBB requires further investigation.
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EHT0202 in Alzheimer’s Disease: A 3-Month,
Randomized, Placebo-Controlled, Double-Blind Study
B. Vellas, O. Sol, P.J. Snyder, P.-J. Ousset,
R. Haddad, M. Maurin, J.-C. Lemarié, L. Désiré,
M.P. Pando and on behalf of EHT0202/002 study group
Background: EHT0202 (etazolate hydrochloride) is
a new compound exhibiting both potential diseasemodifying
and symptomatic treatment properties in Alzheimer’s
Disease increasing alpha-secretase activity and sAPP alpha
secretion, as well as acting as a GABA-A receptor modulator
and as a PDE-4 inhibitor.
Methods: This pilot, randomized, double-blind, placebo-controlled,
parallel group, multicentre, Phase IIA study was conducted
in 159 randomized patients suffering from mild to moderate
Alzheimer’s Disease. EHT0202 (40 or 80mg bid) or placebo
was administered as adjunctive therapy to one acetylcholinesterase
inhibitor over a 3-month period. This study was designed to
assess the clinical safety and tolerability of EHT0202 as
a primary objective, with secondary endpoints (cognitive function,
daily living activities, behaviour, caregiver burden and global
functioning) included to explore clinical efficacy of EHT0202
versus placebo.
Results: EHT0202 was shown to be safe and generally
well tolerated. Dose-dependent numbers of early withdrawal
and central nervous system related adverse events were observed.
As expected, since the study was not powered and not designed
to show drug efficacy, and except for ratings on the ADCS-ADL
scale, no significant differences were seen between treatment
groups.
Conclusions: These first encouraging safety results
do support further development of EHT0202 in order to assess
its clinical efficacy and to confirm its tolerability in a
larger cohort of Alzheimer patients and for a longer period.
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Article]
Neuronal Membranes are Key to the Pathogenesis of
Alzheimer’s Disease: the Role of Both Raft and Non-Raft
Membrane Domains
R. Williamson and C. Sutherland
Membrane rafts are sterol- and sphingolipid-enriched
domains that compartmentalize cellular processes. Membrane
rafts isolated from post-mortem AD brain are enriched in both
β-amyloid
and phosphorylated tau. Proteolytic processing of APP to generate
β-amyloid,
the principle component of amyloid plaques, can occur in membrane
rafts, implicating them in the pathogenesis of Alzheimer’s
disease (AD). Secondary to their role in β-amyloid
generation, membrane rafts have more recently been implicated
in the accumulation, aggregation and degradation of β-amyloid,
with evidence supporting a specific role for membrane raft
gangliosides in the binding and aggregation of β-amyloid.
In addition, membrane domain composition has a direct impact
on both the generation of β-amyloid
and its subsequent toxic actions and as such is a key target
for the development of therapeutic strategies. This mini-review
will focus on recent advances in our understanding of the
relevance of membrane composition, of both raft and non-raft
domains, to AD progression in models and in human disease.
We will discuss how manipulation of membrane composition can
alter both the proteolytic processing of APP and the subsequent
binding and aggregation of β-amyloid
peptide.
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