Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 2, Number 4, October 2005
Contents
Editorial - The A’s and M’s of
Alzheimer’s Disease Pp. 387
Debomoy K. Lahiri
The Role of Apoptotic Pathways in Alzheimer’s
Disease Neurodegeneration and Cell Death Pp. 389
Andrea C. LeBlanc
[Abstract]
Oxidative Stress: The Old Enemy in Alzheimer’s
Disease Pathophysiology Pp. 403
Paula I. Moreira Kazuhiro Honda, Quan Liu, Maria S. Santos,
Catarina R. Oliveira,Gjumrakch Aliev, Akihiko Nunomura, Xiongwei
Zhu, Mark A. Smith and George Perry
[Abstract]
Diversity of Senile Plaques in Alzheimer’s
Disease as Revealed by a New Monoclonal Antibody that Recognizes
an Internal Sequence of the Aβ Peptide Pp. 409
Alberto Rábano, Adolfo Jiménez-Huete, Boris
Acevedo, Miguel Calero, Jorge Ghiso,Israel Valdés,
Jorge Gavilondo, Blas Frangione and Enrique Méndez
[Abstract]
Chitin-like Polysaccharides in Alzheimer’s
Disease Brains Pp. 419
Rudy J. Castellani, Sandra L. Siedlak, Anne E. Fortino,
George Perry, Bernardino Ghetti and Mark A. Smith
[Abstract]
Semantic Memory Disorders in Alzheimer's Disease:
Clues from Semantic Priming Effects Pp. 425
Bénédicte Giffard, Béatrice Desgranges
and Francis Eustache
[Abstract]
Disconnection of Language and Memory in Semantic
Dementia: A Comparative and Theoretical Analysis Pp.
435
Michael J. Passmore, Janet L. Ingles, John D. Fisk and
Sultan Darvesh
[Abstract]
Measuring Morphological and Cellular Changes in
Alzheimer’s Dementia: A Review Emphasizing Stereology
Pp. 449
Anette K. Stark, Dorte P. Pelvig, Anne-Marie B. Jørgensen,
Birgitte B. Andersen and Bente Pakkenberg
[Abstract]
Anticholinesterase and Pharmacokinetic Profile
of Phenserine in Healthy Elderly Human Subjects Pp.
483
Nigel H. Greig, Jon Ruckle, Patrick Comer, Lidia Browne, Harold
W. Holloway,Douglas R. Flanagan Jr. Craig J. Canfield and
Robert G. Burford
[Abstract]
Abstracts
[Back to top]
Editorial - The A’s and M’s of Alzheimer’s
Disease
Debomoy K. Lahiri
We herein present the fourth issue of the second volume of
Current Alzheimer Research. Like the previous issues, our
emphasis remains on presenting exciting and diverse research
on Alzheimer’s disease (AD) that span basic to translational
studies. In this issue, we have selected eight articles from
different emerging areas of AD, including neu-rodegeneration,
brain imaging and drug development. Four articles discuss
four important ‘A’s involved in AD: apop-tosis,
amyloid, antioxidants and anticholinesterases. The remaining
articles highlight the importance of four ‘M’s
in AD: memory (semantic), metals, mitochondria and mor-phometric
studies. Prominent features of AD are synaptic loss, degeneration
of basal forebrain cholinergic neurons and cerebral deposition
of amyloid plaques and tangles. However, presently unclear
are the mechanisms that under-lie this neuronal/synaptic loss
and whether or not this is directly responsible for the progressive
memory dysfunction and dementia of AD. Several of the articles
in this current issue address these questions from mechanistic
(basic), neuropsychological and morphometric perspectives.
LeBlanc summarizes (pp 389-402) the role of apoptotic pathways
in AD neurodegeneration and cell death. She pro-poses an “attrition
hypothesis”: that activation of the effec-tor caspase-6,
due to one or a variety of insults, causes the breakdown of
the cytoskeletal structure of neurites and dam-ages proper
trafficking of proteins and organelles. All these may result
in the observed clinical and pathological features of AD.
Moreira and colleagues (pp 403-408) highlight the mitochondrial
and redox-active metal abnormalities as causes of oxidative
stress in AD. They also discuss the anti-oxidant activity
of both amyloid-β (Aβ) peptide and hyper-phosphorylated
tau, which may normally protect cells against the onslaught
of oxidative insults. The authors argue that in a pathogenic
progression, the compensatory action of these molecules is
lost, resulting in an increase in reactive species and a decrease
in clearance mechanisms. Such events ultimately trigger the
cascade of neurodegeneration typical of AD. Regarding the
characterization of amyloid plaques, Rabano and colleagues
report (pp 409-417) a new monoclonal antibody that recognizes
an internal sequence of the Aβ-peptide that enables researchers
to see the diversity of senile plaques in AD. This would serve
as a powerful research tool in the study of molecular heterogeneity
of plaques both in humans and transgenic mice.
Another major question in the field is the conversion of soluble
Aβ peptide to amyloid deposits. In this context, Cas-tellani
and coworkers describe (pp 419-423) the unique role of polysaccharides
in AD pathogenesis and report the pres-ence of chitin-like
polysaccharides, a highly insoluble poly-mer of N-acetyl glucosamine
linearized by β1-4 linkages. They speculate that this
polysaccharide, which is highly insoluble and a molecular
superstructure for glycan-protein interactions, could provide
a suitable nucleation scaffold for the amyloidosis seen in
AD and other diseases.
AD is basically a memory disorder, which is, conse-quently,
subjected to several important and thorough inves-tigations.
Giffard and colleagues have shed light (pp 425-434) on semantic
memory disorders in AD and, in particu-lar, discuss the utility
of the semantic priming paradigm. Results from semantic priming
are useful to understand the deterioration of the semantic
memory in AD. In a related topic, Passmore and collaborators
present (pp 435-448) an illustrative case of Semantic Dementia
(SD) which they conceptualize as a syndrome of disconnection
between two large distributed cortical networks; namely, between
those networks that subserve language function and those that
subserve memory function. They discuss a comparative and theoretical
analysis relating to the disconnection of language and memory
in SD.
Stark and colleagues (pp 449-481) enlighten the impor-tance
of rigorous approaches in measuring morphological and cellular
changes in Alzheimer’s dementia, with a spe-cial emphasis
placed on human stereological post-mortal studies. The authors
review the limitations of current studies to identify morphometric
correlates with declining cognitive function in normal aging
and AD. These studies rely mostly on semi-quantitative methods
to assess neuropathological markers, such as neurofibrillary
tangles, senile plaques, neuronal or glial cell densities,
and neuron sizes. With some limitations, modern stereological
techniques offer a more rigorous approach for quantifying
neuropathological changes with aging and degenerative diseases,
such as AD.
With regard to translational research and drug discov-ery,
Greig and colleagues (pp 483-492) describe the anticho-linesterase,
pharmacokinetic and safety profile of a novel drug, Phenserine,
in healthy elderly human subjects. In this limited study,
they found that phenserine tartrate was safe and well tolerated
when administered as a single oral dose of either 5 mg or
10 mg.
In future issues of Current Alzheimer Research, we will discuss
AD beyond the letters of ‘A’ and ‘M’.
As an exam-ple, the next issue will feature a “Debate”
section, under which major hypotheses for AD, ‘apoptosis’,
‘tau’, ‘amy-loid’ and ‘non-amyloid’,
will be discussed. Besides the print edition, the journal
is accessible online (http://www. bentham.org/car/). This
site provides free access to ‘Contents and Abstracts’
of all papers published in the different issues of Current
Alzheimer Research. The site is also useful to all authors
for electronic submission of their papers. The jour-nal is
currently abstracted in Biological Abstracts, Chemical Abstracts
and has been approved for listing in MEDLINE by the National
Library of Medicine (NLM), USA.
With your great support, I am very confident that Cur-rent
Alzheimer Research will continue to make a significant contribution
not only in the field of Alzheimer’s disease but in
other neurodegenerative diseases as well. On behalf of the
Editorial Board members and Publishers of the journal, I welcome
your comments, advice, and suggestions to further improve
this journal.
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]
The Role of Apoptotic Pathways in Alzheimer’s
Disease Neurodegeneration and Cell Death
Andrea C. LeBlanc
Neuronal loss is associated with Alzheimer’s disease
(AD). However, it not clear what type of mechanisms underlie
this neuronal loss and if neuronal loss is directly responsible
for the progressive dementia of AD. This review summarizes
the recent evidence for neuronal loss in AD relative to the
level of cognitive impairment. It further describes the current
evidence for an apoptotic mechanism in AD. Lastly, a summary
of the evidence for synaptic loss being responsible for dementia
rather than neuronal loss is presented. A novel hypothesis
emerges from this data to explain all aspects of AD pathophysiology.
This all inclusive hypothesis called the attrition hypothesis
states that activation of the effector caspase-6 in AD due
to one or a variety of insults is responsible for the breakdown
of the cytoskeletal structure of neurites and damages proper
trafficking of proteins and organelles thus resulting in the
observed clinical and patho-logical features of AD.
[Back to top]
Oxidative Stress: The Old Enemy in Alzheimer’s
Disease Pathophysiology
Paula I. Moreira Kazuhiro Honda, Quan Liu, Maria S. Santos,
Catarina R. Oliveira,Gjumrakch Aliev, Akihiko Nunomura, Xiongwei
Zhu, Mark A. Smith and George Perry
The complex nature and genesis of oxidative damage in Alzheimer
disease can be partly answered by mitochondrial and redox-active
metal abnormalities. By releasing high levels of hydrogen
peroxide, dysfunctional mitochondria propagate a series of
interactions between redox-active metals and oxidative response
elements. In the initial phase of disease development, amyloid-β
deposition and hyperphosphorylated τ
may function as compensatory responses and downstream adaptations
to ensure that neuronal cells do not succumb to oxidative
injuries. However, during the pro-gression of the disease,
the antioxidant activity of both agents evolves into pro-oxidant
activity representing a typical gain-of-function transformation,
which can result from an increase in reactive species and
a decrease in clearance mechanisms.
[Back to top]
Diversity of Senile Plaques in Alzheimer’s Disease
as Revealed by a New Monoclonal Antibody that Recognizes an
Internal Sequence of the Aβ Peptide
Alberto Rábano, Adolfo Jiménez-Huete, Boris
Acevedo, Miguel Calero, Jorge Ghiso,Israel Valdés,
Jorge Gavilondo, Blas Frangione and Enrique Méndez
In order to have more specific tools available to approach
amyloidogenesis in Alzheimer’s disease (AD), we have
produced several polyclonal and monoclonal antibodies that
recognize specific sequences of the amyloid β (Aβ)
peptide. Here we present results that demonstrate that our
monoclonal antibody EM5 recognizes an internal sequence (residues
11-16) of the Aβ peptide. This strategic localization
of the epitope allowed us to employ this antibody, together
with two previously reported polyclonal antibodies (EM2 and
EM3, specific for AβX-40 and AβX-42,
respectively), in an immunohistochemical study aimed at exploring
the differential distribution of longer (AβX-40/42)
and shorter (Aβ17-X) peptides along the various
types of amyloid deposits of AD. This antibody panel was used
in six AD brains, on sections from associative neocortex,
striatum and cerebellar cortex. Single and double immunostaining
revealed specific staining of vascular amyloid deposits and
neuritic plaques by EM5 antibody, with high co-localization
of EM2. Our results suggest that EM5 antibody recognizes pathogenic
forms of Aβ deposits (amyloid angiopathy and neuritic
plaques) and reveals the existence of a subset of plaques
with a profile similar to vascular deposits. Additionally,
our results show that diffuse plaques in AD brains may contain
AβM17-X peptides as its principal component.
EM5 may be a useful tool in research both on human and transgenic
mice tissue that may aid in the study of molecular heterogeneity
of plaques in AD.
[Back to top]
Chitin-like Polysaccharides in Alzheimer’s Disease
Brains
Rudy J. Castellani, Sandra L. Siedlak, Anne E. Fortino,
George Perry, Bernardino Ghetti and Mark A. Smith
The role of polysaccharides in the pathogenesis of Alzheimer
disease (AD) is unclear. However, in light of studies indicating
impaired glucose utilization in AD and increased activation
of the hexosamine pathway that is seen with hyperglycemia,
in the brains of patients with AD, aberrantly high levels
of glucosamine may result in synthesis of glucosamine polymers
such as chitin, a highly insoluble polymer of N-acetyl glucosamine,
linearized by β1-4 linkages. To examine this further,
we studied brain tissue at autopsy from subjects with sporadic
and familial AD using calcofluor histochemistry. Calcofluor
excites on exposure to ultraviolet light and exhibits a high
affinity for chitin in vivo by inter-acting with
β1-4 linkages. Amyloid plaques and blood vessels affected
by amyloid angiopathy showed bright fluores-cence. Moreover,
treatment with chitinase, followed by β-N-acetyl glucosaminidase
showed a decrease in calcofluor fluorescence. Since chitin
is a highly insoluble molecule and a substrate for glycan-protein
interactions, chitin-like poly-saccharides within the brain
could facilitate nucleation of amyloid proteins in various
amyloidoses including AD.
[Back to top]
Semantic Memory Disorders in Alzheimer's Disease:
Clues from Semantic Priming Effects
Bénédicte Giffard, Béatrice Desgranges
and Francis Eustache
Semantic memory deficits are a common landmark in Alzheimer’s
disease, but the nature of these impairments remains to be
clarified. The tests used to explore this memory system are
not specific and involve cognitive processes often disturbed
in Alzheimer’s disease. A complementary way to investigate
semantic memory in neuropsychology is by using the semantic
priming paradigm. Here, semantic priming refers specifically
to the modification of a stimulus processing behind the presentation
of a related stimulus; it is a short-lived phenomenon considered
an implicit measure of semantic memory integrity. However,
semantic priming studies have yielded contradictory results
in Alzheimer’s disease, with authors reporting normal
priming, less-than-normal priming, or increased priming effects
(hyperpriming). The aim of this paper is to review the literature
investigating semantic priming in Alzheimer’s disease,
and to discuss the contradictory results in the context of
current models of semantic processing. For a clear comprehension
of the semantic priming patterns in this pathology, we will
precise the methodology used and the characteristics of the
Alzheimer’s dis-ease patients examined. Besides, the
surprising hyperpriming phenomenon – often observed
in Alzheimer’s disease at the early stage of dementia
– will also be explained in detail. These results from
semantic priming represent invaluable clues to widen our knowledge
and conceptions about deterioration of the semantic memory
in Alzheimer’s disease.
[Back to top]
Disconnection of Language and Memory in Semantic Dementia:
A Comparative and Theoretical Analysis
Michael J. Passmore, Janet L. Ingles, John D. Fisk and
Sultan Darvesh
In this paper, we present an illustrative case of Semantic
Dementia (SD) and we review the literature on this relatively
rare progressive neurodegenerative disorder. After reviewing
the clinical, neuroimaging, neuropathological, and genetic
features of SD, we propose a theoretical framework that addresses
features of SD and relates them to features of other well
known neuropsychiatric syndromes. Our ‘on-line / off-line
disconnection’ model seeks to conceptualize SD as a
syndrome of disconnection between two large distributed cortical
networks, namely, between those networks that subserve language
function and those that subserve memory function.
[Back to top]
Measuring Morphological and Cellular Changes in Alzheimer’s
Dementia: A Review Emphasizing Stereology
Anette K. Stark, Dorte P. Pelvig, Anne-Marie B. Jørgensen,
Birgitte B. Andersen and Bente Pakkenberg
From a clinical as well as a neuropathological point of
view Alzheimer’s disease (AD) has been the focus of
intense research for more than three decades. Most studies
to identify morphometric correlates with the declining cognitive
function in normal aging and AD have employed semi-quantitative
methods to assess neuropathological markers such as neurofibrillary
tangles, senile plaques, neuronal, or glial cell densities,
and neuron sizes. To this end, many cell counting methods
have employed two-dimensional designs in single sections,
yielding estimates of cell numbers either as neuron densities
(number of cell profiles per area) or estimates of the size
distribution of neuron profiles in columns vertical to the
cortical surface. This approach gives rise to difficulties
in interpretation because of the three-dimensional size, shape,
and orientation of the counted cells, and the effect of shrinkage
artifacts.
Modern stereological techniques offer a more rigorous approach
for quantifying neuropathological changes associated with
aging and degenerative disease. However the stereological
studies also suffer from the limitations of high biological
variability in AD-type neuropathology, and the relative scarcity
of autopsied brains from well-studied non-demented comparison
subjects. As a result, the clinicopathological associations
between neuropathology and indices of cognitive performance
in aging and AD are not yet firmly established. The requirement
for the proper description of morphologic neuropathology of
AD is clear: any macroscopic or microscopic abnormalities,
are subtle and must consequently be demonstrated reproducibly
in well-controlled studies. In this review we try to evaluate
which, if any, of the contemporary claims for morphometric
brain abnormalities in AD can be said to be well established,
with special emphasis placed on human stereological post-mortal
studies.
[Back to top]
Anticholinesterase and Pharmacokinetic Profile of
Phenserine in Healthy Elderly Human Subjects
Nigel H. Greig, Jon Ruckle, Patrick Comer, Lidia Browne,
Harold W. Holloway,Douglas R. Flanagan Jr. Craig J. Canfield
and Robert G. Burford
Objective: To evaluate the safety, maximum
tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics
(PD) of the acetyl-selective anticholinesterase, phenserine
tartrate, in healthy elderly subjects.
Methods: 32 healthy elderly volunteers received
single oral doses of phenserine tartrate (5–20 mg).
Physical and vital signs were monitored over the ensuing 24
hours. Analyses were performed on plasma samples to determine
PK, and PD were assessed using an erythrocyte acetylcholinesterase
(AChE) inhibition assay.
Results: No serious adverse events (AEs)
occurred; the most common were headache and vomiting. The
MTD of phen-serine tartrate was 10 mg. The Cmax
and AUC(0–24) of phenserine increased with dose, but
neither were dose-proportional. Subjects receiving 10 mg of
phenserine tartrate had a Cmax of 1.95 ng/mL at
1.5 hours, and the mean peak inhibition (Imax)
of AChE was 26% (range: 18–34%) at 1.75 hours (tImax)
following dosing. The half-life of AChE inhibi-tion (tI1/2)
was 11 hours. Evaluation of PK/PD relationships suggested
a linear correlation between plasma phenserine concentration
and AChE inhibition in the blood.
Conclusions: Phenserine tartrate was safe
and well tolerated when administered as a single oral dose
of either 5 mg or 10 mg. An increase in the severity and frequency
of AEs occurred at the 20 mg dose level.
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