| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 3, Number 5, December 2006
Contents
“Alzheimer’s Disease: A Centennial
Issue”
Guest Editor: Frank M. LaFerla
Editorial
Marking the Centennial of Alzheimer’s First Report of
the Disease with a Perspective of Ongoing Research and Future
Challenge Pp. 409-410
Debomoy K. Lahiri and Frank M. LaFerla
Alzheimer’s and Dementia in the Oldest-Old:
A Century of Challenges Pp. 411-419
Claudia H. Kawas and Maria M. Corrada
[Abstract]
Filling the Gaps in the Aβ
Cascade Hypothesis of Alzheimer’s Disease Pp.
421-435
Todd E. Golde, Dennis Dickson and Michael Hutton
[Abstract]
Proteolytic Degradation of the Amyloid β-Protein:
The Forgotten Side of Alzheimer’s Disease Pp.
431-435
Malcolm A. Leissring
[Abstract]
Pathways by Which Aβ
Facilitates Tau Pathology Pp. 437-448
Mathew Blurton-Jones and Frank M. LaFerla
[Abstract]
The Role of Tau Phosphorylation in the Pathogenesis
of Alzheimer’s Disease Pp. 449-463
Kaihong Mi and Gail V.W. Johnson
[Abstract]
Genetic and Environmental Modifiers of Alzheimer’s
Disease Phenotypes in the Mouse Pp. 465-473
Davis Ryman and Bruce T. Lamb
[Abstract]
Taking Down the Unindicted Co-Conspirators of Amyloid
β-Peptide-mediated
Neuronal Death: Shared Gene Regulation of BACE1 and APP Genes
Interacting with CREB, Fe65 and YY1 Transcription Factors
Pp. 475-483
Debomoy K. Lahiri, Yuan-Wen Ge, Jack T. Rogers, Kumar
Sambamurti, Nigel H. Greig and Bryan Maloney
[Abstract]
Progranulin Mutations in Ubiquitin-Positive Frontotemporal
Dementia Linked to Chromosome 17q21 Pp. 485-491
Marc Cruts, Samir Kumar-Singh and Christine Van Broeckhoven
[Abstract]
Computer Simulations of Alzheimer’s Amyloid
β-Protein
Folding and Assembly Pp 493-504
Brigita Urbanc, Luis Cruz, David B. Teplow and H. Eugene
Stanley
[Abstract]
A Role for TGF-β
Signaling in Neurodegeneration: Evidence from Genetically
Engineered Models Pp. 505-513
Ina Tesseur and Tony Wyss-Coray
[Abstract]
Mitochondrial Dysfunction and Alzheimer’s Disease
Pp. 515-520
Xi Chen, David Stern and Shi Du Yan
[Abstract]
Beta-Amyloid, Oxidative Stress and Down Syndrome
Pp. 521-528
Ira T. Lott, Elizabeth Head, Eric Doran and Jorge Busciglio
[Abstract]
Imaging the Earliest Stages of Alzheimer’s Disease
Pp. 529-539
William Wu and Scott A. Small
[Abstract]
The Path from Anti Parkinson Drug Selegiline and Rasagiline
to Multifunctional Neuroprotective Anti Alzheimer Drugs Ladostigil
and M30 Pp. 541-550
Moussa B.H. Youdim
[Abstract]
Abstracts
[Back to top]
Editorial: Marking the Centennial of Alzheimer’s First
Report of the Disease with a Perspective of Ongoing Research
and Future Challenge
Debomoy K. Lahiri and Frank M. LaFerla
Current Alzheimer Research presents the fifth
issue of its third volume and this special issue is meant
to mark the centennial of Alois Alzheimer’s original
description of the disease that would come to bear his name.
How best can one commemorate this seminal discovery? Since
the field has become quite diverse and large, it is difficult
to accommodate all the fascinating areas of Alzheimer’s
disease (AD), nor could we invite contributions from all the
respective field’s leading scientists within a limited
space of the special issue. Instead of adopting the historical
approach, we have invited selected leaders in the field to
share their work with the readers of the journal in order
to capture a glimpse of current research on AD. We review
the progress of a sample of cutting-age work in various aspects
of the disorder in terms of mechanism and therapeutic implication.
The articles in this special issue cover a wide range of cellular,
molecular and animal-based research, ranging from the roles
of amyloid, tau protein, genetics and oxidative stress to
brain imaging on neurobiology and pathogenesis of AD using
innovative experimental models.
AD is the most common form of dementia in the US and most
of the world, with rates increasing exponentially from age
65. A significant increase in life expectancy during the last
century has resulted in a large number of people living to
old age, and this will cause a quadrupling of AD cases by
the middle of the century. Therefore, a systematic study of
the disease is of paramount importance to understand the neurobiology,
genetics and environmental risk factors of AD; these studies
will lead to development of effective drug targets and therapeutic
approaches.
The present issue reports fourteen articles discussing the
most exciting and relevant topics in the field of AD. The
first article is a timely review by Kawas and Corrada (page
411-419) on the ‘90+ Study’ to address some of
the unanswered questions about AD and dementia in the oldest-old.
Since the initial description one hundred years ago by Alzheimer,
the disorder is still being mainly characterized by the occurrence
of two brain lesions: amyloid plaques and neurofibrillary
tangles (NFTs). From that time, onwards, a significant advance
has been made in characterization of these lesions and their
role in AD pathogenesis, employing different cellular and
animal models. For example, amyloid plaques have been shown
mostly to comprise amyloid β-peptide
(Aβ),
whereas NFTs are composed of hyperphosphoryalted tau proteins.
However, the precise relationship between Aβ
and tau, the two proteins that accumulate within the brain
lesions, is just beginning to be understood. Two papers discuss
about the production of Aβ,
and its proteolytic degradation. Golde et al. present
(page 421-430) different aspects of the ‘Aβ
Cascade Hypothesis’ of AD, and argue for an array of
therapeutic interventions that could target Aβ
metabolism. In addition to Aβ
production, Leissring emphasizes (page 431-435) the role of
Aβ
clearance (proteolytic degradation) by Aβ-degrading
proteases in AD. The relationship between Aβ
and tau proteins is the subject matter of another set of two
papers. Blur-ton-Jones and LaFerla discuss (page 437-448)
how Aβ
accumulation facilitates tau pathology, whereas Mi and Johnson
describe (page 449-463) the role of tau phosphorylation in
AD pathogenesis. In addition to neuropathological markers,
genetic and environmental factors are elucidated. Ryman and
Lamb analyze (page 465-473) the implications of genetic modifiers
for mouse and human AD research, and responsiveness to environmental
or treatment interventions. A detailed molecular analysis
by Lahiri et al. (page 475-484) of an important gene,
beta secretase (BACE1), reveals potential drug targets within
the BACE1 regulatory region. Cruts and colleagues narrate
(page 485-491) the discovery of novel genetic mutations in
frontotempral dementia, and such work represents how far genetic
research has progressed in the field of neurodegeneration
and AD over the years.
But genes are not the only culprits as steps can go awry down
at the protein level during the disease process. Urbane and
colleagues update (page 493-504) on proper protein folding
and assembly and their role in AD, which represent an important
area of current research. Apart from the characteristic β-amyloid
and tau proteins, Tesseur and Wyss-Coray highlight (page 505-513)
the role of trophic factors and dysregulation of TGF-β
signaling in neurodegeneration. Cell signaling to mitochondria
and oxidative stress constitute two other important articles.
Chen et al. emphasize (page 515-520) the role of
mitochondrial dysfunction in AD, whereas Lott et al.
highlight (page 521-528) the interplay of Aβ
and oxidative stress in Down syndrome (DS). As the authors
rightly point out, since the pathological processes leading
to AD are present in DS, there is an opportunity for early
pharmacological intervention in the disorder.
The journey from the histological stains used by Alois Alzheimer
100 years ago to ‘functional’ imaging techniques
is quite fascinating and has indeed advanced the AD field
enormously. Wu and Small (page 529-539) trace the technical
innovations in brain imaging that might probably detect early
stages of the disease. Our final article, by Youdim (page
541-550), illustrates how the pathology of AD as well as cascade
of events that lead to the neurodegenerative process can be
used to develop multifunctional neuroprotective CNS targeting
drugs with possible disease modifying activity.
These articles bring to neuroscientists, clinicians and interested
individuals a perspective of past work and a glimpse of current
research and future opportuni-ties in the AD field. This special
issue serves as a sample of the modern basic and translational
research in the AD field and provides a strong template for
other important future discoveries. A small but significant
step by Alzheimer a century ago has definitely made a significant
impact in understanding the complex pathology of this devastating
disease and with the advances of innovative research, hopefully,
potential drug development strategies will eventually emerge.
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
Frank M. LaFerla
Department of Neurobiology & Behavior
University of California, Irvine
Irvine, Cailfornia-92697
USA
[Back to top]
Alzheimer’s and Dementia in the Oldest-Old:
A Century of Challenges
Claudia H. Kawas and Maria M. Corrada
Alzheimer’s disease (AD) is the most common type of
dementia in the US and much of the world with rates increasing
exponentially from age 65. Increases in life expectancy in
the last century have resulted in a large number of people
living to old ages and will result in a quadrupling of AD
cases by the middle of the century. Preventing or delaying
the onset of AD could have a huge impact in the number of
cases expected to develop. The oldest-old are the fastest
growing segment of the population and are estimated to account
for 12% of the population over 65. Establishing accurate estimates
of dementia and AD rates in this group is crucial for public
health planning. Prevalence and incidence estimates above
age 85 are imprecise and inconsistent because of the lack
of very old individuals in most studies. Moreover, risk and
protective factors in our oldest citizens have been studied
little, and clinical-pathological correlations appear to be
poor. We introduce The 90+ Study, established to address some
of the unanswered questions about AD and dementia in the oldest-old.
Our preliminary results show that close to half of demented
oldest-old do not have known cerebral pathology to account
for their cognitive deficits. Furthermore, the APOE-e4 allele
appears to be a risk factor for AD only in the women in our
study. In addition to the challenge of preventing and treating
AD, the oldest-old will require major investigative energy
to better understand the concomitants of longevity, the causes
of dementia, and the factors that promote successful aging
in oldest citizens.
[Back to top]
Filling the Gaps in the Aβ
Cascade Hypothesis of Alzheimer’s Disease
Todd E. Golde, Dennis Dickson and Michael Hutton
Advances in the understanding of Alzheimer’s disease
(AD) pathogenesis provide strong support for a modified version
of the amyloid cascade hypothesis, which is now often referred
to as the amyloid β
protein (Aβ)
cascade hypothesis. The basic tenant of this modified hypothesis
is that Aβ
aggregates trigger a complex pathological cascade leading
to neurodegeneration. Thus, as opposed to the original amyloid
hypothesis, whose basic tenant was that amyloid deposits cause
AD, the Aβ
hypothesis is more inclusive in that it takes into account
the possibility that several different Aβ
assemblies might contribute to AD pathogenesis and not merely
the detectable amyloid deposits within the brain. Significantly,
the Aβ
hypothesis has provided the rationale for a plethora of therapeutic
interventions that target Aβ
production, aggregation or clearance. Indeed, AD research
is entering an exciting phase in which strategies derived
from basic research will be tested in humans. Despite this
progress, many aspects of AD pathogenesis, particularly those
downstream of Aβ
accumulation are not well understood. Herein, we explore several
observations that serve to illustrate the more enigmatic aspects
of the Aβ
hypothesis, and discuss why further basic research may be
critical in order to develop therapies designed to halt neurodegeneration
and reverse cognitive decline in patients already suffering
from AD dementia.
[Back to top]
Proteolytic Degradation of the Amyloid β-Protein:
The Forgotten Side of Alzheimer’s Disease
Malcolm A. Leissring
Proteases have long played a central role in the molecular
pathogenesis of Alzheimer’s disease (AD), yet proteases
that degrade the amyloid β-protein
(Aβ)
itself were largely ignored until only quite recently. Today,
we know that Aβ-degrading
proteases are critical regulators of brain Aβ
levels in vivo, with evidence accumulating that their
dysfunction may play a role in the etiology of AD. This review
explores the historical factors that obscured this important
aspect of amyloidogenesis, and discusses the many fresh insights
it offers into the causes of and potential treatments for
AD.
[Back to top]
Pathways by Which Aβ
Facilitates Tau Pathology
Mathew Blurton-Jones and Frank M. LaFerla
Since the initial description one hundred years ago by Dr.
Alois Alzheimer, the disorder that bears his name has been
characterized by the occurrence of two brain lesions: amyloid
plaques and neurofibrillary tangles (NFTs). Yet the precise
relationship between beta-amyloid (Aβ)
and tau, the two proteins that accumulate within these lesions,
has proven elusive. Today, a growing body of work supports
the notion that Aβ
may directly or indirectly interact with tau to accelerate
NFT formation. Here we review recent evidence that Aβ
can adversely affect distinct molecular and cellular pathways,
thereby facilitating tau phosphorylation, aggregation, mis-localization,
and accumulation. Studies are presented that support four
putative mechanisms by which Aβ
may facilitate the development of tau pathology. A great deal
of work suggests that Aβ
may drive tau pathology by activating specific kinases, providing
a straightforward mechanism by which Aβ
may enhance tau hyperphosphorylation and NFT formation. In
the AD brain, Aβ
also triggers a massive inflammatory response and pro-inflammatory
cytokines can in turn indirectly modulate tau phosphorylation.
Mounting evidence also suggests that Aβ
may inhibit tau degradation via the proteasome. Lastly, Aβ
and tau may indirectly interact at the level of axonal transport
and evidence is presented for two possible scenarios by which
axonal transport deficits may play a role. We propose that
the four putative mechanisms described in this review likely
mediate the interactions between Aβ
and tau, thereby leading to the development of AD neurodegeneration.
[Back to top]
The Role of Tau Phosphorylation in the Pathogenesis
of Alzheimer’s Disease
Kaihong Mi and Gail V.W. Johnson
The microtubule-associated protein tau, which is abundantly
expressed in neurons, is deposited in cells in an abnormally
phosphorylated state as fibrillar lesions in numerous neurodegenerative
diseases, with the most notable being Alzheimer's disease.
Tau plays a crucial role in the neuron as it binds and stabilizes
microtubules, and can regulate axonal transport; functions
that are regulated by site-specific phosphorylation events.
In pathological conditions such as Alzheimer’s disease
and other tauopathies, tau is abnormally phosphorylated, and
that this contributes to its dysfunction. Given the increasing
evidence that a disruption in the normal phosphorylation state
of tau followed by conformational changes plays a key role
in the pathogenic events that occur in Alzheimer's disease
and other tauopathies; it is critical to elucidate the regulation
of tau phosphorylation. This review focuses on recent literature
pertaining to the regulation of tau phosphorylation and function,
and the role that a dysregulation of tau phosphorylation may
play in the neuronal dysfunction in Alzheimer’s disease.
[Back to top]
Genetic and Environmental Modifiers of Alzheimer’s
Disease Phenotypes in the Mouse
Davis Ryman and Bruce T. Lamb
As a group, strains of laboratory mice carrying Alzheimer’s
disease (AD)-related transgenes are currently the most widely
studied animal models of AD. Many AD mouse models carrying
the same or similar transgene constructs demonstrate strikingly
different phenotypic responses to transgene expression, mimicking
the apparent genetic complexity of AD pathogenesis seen in
the human population. Genetic differences between the numerous
mouse model strains used for AD research can significantly
affect correct interpretation and cross-comparison of experimental
findings, making genetic background an important consideration
for all work in mouse models of AD. Furthermore, because of
the potential for discovering novel genetic modifiers of AD
pathogenesis, the effects of genetic background on AD phenotypes
in the mouse can prove a worthwhile subject of study in their
own right. This review discusses the implications of genetic
modifiers for mouse and human AD research, and summarizes
recent findings identifying significant roles for genetic
back-ground in modifying important phenotypes in AD mouse
models, including premature death, amyloid deposition, tau
hyperphosphorylation, and responsiveness to environmental
or treatment interventions.
[Back to top]
Taking Down the Unindicted Co-Conspirators of Amyloid
β-Peptide-mediated
Neuronal Death: Shared Gene Regulation of BACE1 and APP Genes
Interacting with CREB, Fe65 and YY1 Transcription Factors
Debomoy K. Lahiri, Yuan-Wen Ge, Jack T. Rogers, Kumar
Sambamurti, Nigel H. Greig and Bryan Maloney
Major hallmarks of Alzheimer’s disease (AD) include
brain deposition of the amyloid–β
peptide (Aβ),
which is proteolytically cleaved from a large Aβ
precursor protein (APP) by β
and γ –
secretases. A transmembrane aspartyl protease, β–APP
cleaving enzyme (BACE1), has been recognized as the β–secretase.
We review the structure and function of the BACE1 protein,
and of 4129 bp of the 5’–flanking region sequence
of the BACE1 gene and its interaction with various transcription
factors involved in cell signaling. The promoter region and
5’–untranslated region (UTR) contain multiple
transcription factor binding sites, such as AP–1, CREB
and MEF2. A 91 bp fragment is the shortest region with significant
reporter gene activity and constitutes the minimal promoter
element for BACE1. The BACE1 promoter contains six unique
functional domains and three structural domains of increasing
sequence complexity as the “ATG” start codon is
approached. Notably, the BACE1 gene promoter contains basal
regulatory elements, inducible features and sites for regulation
by various important transcription factors. Herein, we also
discuss and speculate how the interaction of these transcription
factors with the BACE1 promoter can modulate synaptic plasticity,
neuronal apoptosis and oxidative stress, which are pertinent
to the pathogenesis and progression of AD.
[Back to top]
Progranulin Mutations in Ubiquitin-Positive Frontotemporal
Dementia Linked to Chromosome 17q21
Marc Cruts, Samir Kumar-Singh and Christine Van Broeckhoven
Two genetically distinct types of frontotemporal dementia
(FTD) are linked to chromosome 17q21. FTD with parkinsonism
(FTDP-17) results from mutations in the gene encoding microtubule
associated protein tau (MAPT) and is associated with
tau deposition in the patient’s brain. An increasing
number of FTD families are linked to 17q21 in the absence
of a demonstrable MAPT mutation. Brains of these
patients do not show tau deposits, but tau-negative intra-
and perinuclear inclusions of unknown composition that are
immunoreactive to ubiquitin (FTDU-17). These ubiquitin inclusions
are located in the cytoplasm or nucleus of predominantly neuronal
cells of affected brain regions. By extensive segregation
analyses in conclusively linked FTDU-17 families, the candidate
region was reduced to a 6.2 Mb segment containing MAPT;
however, genomic sequencing of MAPT in FTDU-17 patients
excluded disease-causing mutations. Further, the linked region
was characterized by the presence of multiple low-copy repeat
regions associated with genomic instability. However, we excluded
genomic rearrangements as the cause of FTDU-17. Subsequent
sequencing of positional candidate genes identified loss-of-function
mutations in the gene encoding progranulin (PGRN),
a growth factor involved in multiple physiological processes
such as cellular proliferation and survival and tissue repair,
and pathological processes including tumorigenesis. In a Belgian
FTD patient series, the prevalence of PGRN mutations
was 3.5 times higher than that of MAPT mutations
underscoring a major role for PGRN in FTD pathogenesis.
Together, mutation data provided convincing evidence that
PGRN haploinsufficiency leads to neurodegeneration
because of reduced PGRN-mediated neuronal survival. The PGRN
protein is not deposited in the ubiquitin-positive inclusions,
the nature of which remains unknown. Due to the functions
of PGRN in neuronal survival and the clinicopathological overlaps
between FTD and other dementias it is likely that reduced
PGRN expression is associated with the progression
of other neurodegenerative brain diseases including Alzheimer’s
disease. These findings open promising novel targets for therapeutic
intervention against neurode-generation.
[Back to top]
Computer Simulations of Alzheimer’s Amyloid
β-Protein
Folding and Assembly
Brigita Urbanc, Luis Cruz, David B. Teplow and H. Eugene
Stanley
Pathological folding and aggregation of the amyloid β-protein
(Aβ)
are widely perceived as central to understanding Alzheimer’s
disease (AD) at the molecular level. Experimental approaches
to study Aβ
self-assembly are limited, because most relevant aggregates
are quasi-stable and inhomogeneous. In contrast, simulations
can provide significant insights into the problem, including
specific sites in the molecule that would be attractive for
drug targeting and details of the assembly pathways leading
to the production of toxic assemblies. Here we review computer
simulation approaches to understanding the structural biology
of Aβ.
We discuss the ways in which these simulations help guide
experimental work, and in turn, how experimental results guide
the development of theoretical and simulation approaches that
may be of general utility in understanding pathologic protein
folding and assembly.
[Back to top]
A Role for TGF-β
Signaling in Neurodegeneration: Evidence from Genetically
Engineered Models
Ina Tesseur and Tony Wyss-Coray
Neurodegenerative diseases including Alzheimer’s disease
(AD) and Parkinson’s disease (PD) afflict growing numbers
of people but treatments are not available or ineffective.
These diseases are characterized by the loss of specific neuronal
populations, the accumulation of protein aggregates inside
and sometimes outside neurons, and an activation of immune
pathways in the brain. The causes of sporadic forms of AD
or PD are not known but it has been postulated that reduced
trophic support to neurons together with age dependent increases
in cellular stress lead to chronic injury and ultimately the
demise of neurons. TGF-βs
are neuroprotective factors and organizers of injury responses
and as such might have a role in neurodegenerative disease.
We review here the evidence mostly from genetically manipulated
mice that links the TGF-β
signaling pathway to neuronal phenotypes and neurodegeneration.
Although many of these mutant models did not produce overt
CNS phenotypes or adult brain were not studied due to embryonic
lethality, there is growing support for a role of TGF-β
signaling in neuronal maintenance, function, and degeneration.
Future studies will have to determine whether dysregulation
of TGF-β
signaling in neurodegenerative diseases is significant and
whether this signaling pathway may even be a target for treatment.
[Back to top]
Mitochondrial Dysfunction and Alzheimer’s Disease
Xi Chen, David Stern and Shi Du Yan
Mitochondrial dysfunction has been implicated in causing metabolic
abnormalities in Alzheimer’s disease (AD). The searches
for mitochondrial DNA variants associated with AD susceptibility
have generated conflicting results. The age-related accumulation
of somatic mitochondrial DNA deletion has been suggested to
play a pathogenic role in the development of AD. Recent studies
have demonstrated that amyloid-beta peptide (Aβ)
progressively accumulates in mitochndrial matrix, as demonstrated
in both transgenic mice over-expressing mutant amyloid precursor
protein (APP) and autopsy brain from AD patients. Aβ-mediated
mitochondrial stress was evidenced by impaired oxygen consumption
and decreased respiratory chain complexes III and IV activities
in brains from AD patients and AD-type transgenic mouse model.
Furthermore, our studies indicated that interaction of intramitochondrial
Aβ
with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase
(ABAD), inhibits its enzyme activity, enhances generation
of reactive oxygen species (ROS), impairs energy metabolism,
and exaggerates Aβ-induced
spatial learning/memory deficits and neuropathological changes
in transgenic AD-type mouse model. Interception of ABAD-Aβ
interaction may be a potential therapeutic strategy for Alzheimer’s
disease.
[Back to top]
Beta-Amyloid, Oxidative Stress and Down Syndrome
Ira T. Lott, Elizabeth Head, Eric Doran and Jorge Busciglio
Down syndrome (DS) provides a model for studying important
aspects of Alzheimer disease (AD). Chromosome 21 contains
several genes that have been implicated in neurodegenerative
mechanisms. These include Cu/Zn superoxide dismutase (SOD-1),
Ets-2 transcription factors, Down Syndrome Critical Region
1 (DSCR1) stress-inducible factor, and the amyloid precursor
protein (APP). The accumulation of Aβ
plaques is progressive across the lifespan in DS. Over-expression
of APP in the obligate region for DS is associated with abundant
Aβ
plaques and tangles consistent with Braak stage V-VI. Intraneuronal
Aβ
in DS appears to trigger a pathological cascade leading to
oxidative stress and a neurode-generation typical of AD. There
are suggestions that an increase in subcellular processing
of APP and factors related to membrane APP cleavage favor
the secretion of Aβ
with age in DS. A misbalance between SOD-1 and glutathione
peri-oxidase activity in DS has been linked to free radical
generation. Ets-2 and DSCR1 overexpression in DS has been
linked to cell degeneration. Age-related accumulation of somatic
DNA mutations in both DS and AD contribute to oxidative stress
that exacerbates the imbalance in gene expression. This leads
to enhanced Aβ
deposition and further neuronal vulnerability. The consequence
of these factors and their temporal relationships is likely
to be the subject of future research. Since the pathological
processes leading to AD are seen across the lifespan in DS,
an opportunity is afforded for early pharmacological intervention
in the disorder.
[Back to top]
Imaging the Earliest Stages of Alzheimer’s Disease
William Wu and Scott A. Small
Historical progress in medicine can be charted along the lines
of technical innovations that have visualized the invisible.
One hundred years ago, Alois Alzheimer exploited newly developed
histological stains to visualize his eponymonous disease in
dead tissue under the microscope. Now, as we are entering
the second century of Alzheimer’s disease research,
technical innovation has endowed us with a range of in
vivo imaging techniques that promise to visualize Alzheimer’
disease in living people. The earliest stage of Alzheimer’s
disease is characterized by cell-sickness, not cell-death,
and can occur before the deposition of amyloid plaques or
neurofibrillary tangles. In principle, ‘functional’
imaging techniques might be able to detect this early stage
of the disease, a stage that was invisible to Alzheimer himself.
Here, we will first define the neurobiological meaning of
‘function’ and then review the different approaches
that measure brain dysfunction in Alzheimer’ disease.
[Back to top]
The Path from Anti Parkinson Drug Selegiline and Rasagiline
to Multifunctional Neuroprotective Anti Alzheimer Drugs Ladostigil
and M30
Moussa B.H. Youdim
The therapeutic use of enzyme inhibitors in treatment of neurodegenerative
diseases has its origin in the anti Parkinson action of the
selective monoamine oxidase (MAO) B inhibitor, l-deprenyl
(selegiline ), a failed anti depressant in 1975. This led
to further development of MAO- A and B, catechol-O-methyltansferase
and cholinestrerase inhibitors as anti Parkinson and Alzheimer
drugs. One of the main reasons for the cognitive deficit in
dementia of the Alzheimer’ type (AD) and in dementia
with Lewy bodies (DLB) is degeneration of cholinergic cortical
neurones and synaptic plasticity. This led to a correlation
that similar to Parkinson’s Disease (PD), cholinesterase
inhibitors (ChEI) may also have therapeutic activity in AD.
Significant percentage of AD and DLB subjects also nigrostriatal
dopaminergic, locus ceruleous noradrenergic and raphe nucleus
serotoninergic neurones. The present ChEI anti AD drugs have
limited symptomatic activity and devoid of neuroprotective
property that is needed for disease modifying action. It is
becoming clear that there are no magic bullets for neurodegenerative
disorders and shut gun approach is needed either as polypharmacology
or drugs with multiple activity at different target sites
in the CNS. The complex pathology of AD as well as cascade
of events that leads to the neurodegenerative process has
led us to develop several multifunctional neuroprotective
drugs with several CNS targets with possible disease modifying
activity. Employing the pharamcophore of our antiparkinson
drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan)
we have developed a novel multifunctional neuroprotective
drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl
methylcarbamate)], with both cholinesterase-butyrylesterase
(Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory
activities possessing the neuroprotective-neurescue propargyl
moiety, as potential treatment of AD and DLB and PD with dementias.
Since brain MAO and iron increase in AD, PD and ageing, that
could lead to iron dependent oxidative stress neurodegeneration,
we have developed another series of multifunctional drugs
(M30 HLA-20 series) which are brain permeable iron chelators-
brain selective MAO inhibitors and possess the propargyl neuroprotective
moiety. These series of drugs have the ability of regulating
and processing APP (amyloid precursor protein) and reducing
Aβ
peptide, since APP is a metaloprotein, with an iron responsive
element 5”UTR similar to transferring and ferritin.
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