| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 3, Number 2, April 2006
Contents
Editorial - Update on Current Alzheimer Research
Pp. 93-94
Debomoy K. Lahiri
Vicious Cycles Within the Neuropathophysiologic
Mechanisms of Alzheimer’s Disease Pp. 95-107
John B. Standridge
[Abstract]
Alzheimer’s Disease – An Interactive
Perspective Pp. 109-121
Klaus Heese and Hiroyasu Akatsu
[Abstract]
Inhibition of GSK3 Dependent Tau Phosphorylation
by Metals Pp. 123-127
Alberto Gómez-Ramos, Jorge Domínguez, Delia
Zafra, Helena Corominola, Ramon Gomis, Joan J. Guinovart and
Jesús Avila
[Abstract]
Treating Alzheimer’s Disease by Inactivating
Bioactive Amyloid β
Peptide Pp. 129-135
Yuanbin Liu and David Schubert
[Abstract]
Pharmacological Manipulation of the Vasoconstrictive
Effects of Amyloid-β
Peptides by Donepezil and Rivastigmine Pp. 137-145
Goksel Doganay, Bereha Khodr, George Georgiou
and Zeinab Khalil
[Abstract]
Cholinesterase Inhibitors Slow Decline in Executive
Functions, Rather than Memory, in Alzheimer’s Disease:
A 1-Year Observational Study in the Sunnybrook Dementia Cohort
Pp. 147-156
Pearl Behl, Krista L. Lanctôt, David L.
Streiner, Isabelle Guimont and Sandra E. Black
[Abstract]
Studies on the Effect of the Apolipoprotein E
Genotype on the Lipid Profile in Alzheimer’s Disease
Pp. 157-160
Marwan N. Sabbagh, Shawn Sandhu, Heather Kolody,
Tyson Lahti, Nina B. Silverberg and D. Larry Sparks
[Abstract]
Predictors of Conversion to Dementia of Probable
Alzheimer Type in Patients with Mild Cognitive Impairment
Pp. 161-170
Pedro J. Modrego
[Abstract]
Commentary - The Renin Angiotensin System in Alzheimer’s
Disease – Do Updates Highlight a Clinical and Biological
Dichotomy? Pp. 171-173
Patrick G. Kehoe and Gordon K. Wilcock
[Abstract]
Abstracts
[Back to top]
Editorial - Update on Current Alzheimer Research
Current Alzheimer Research presents the second
issue of its third volume, which comprises nine articles from
both primary research and review work. These articles report
a combination of mechanism-based and clinically-oriented translational
studies that cover a wide range of Alzheimer’s disease
(AD) research from the cholinergic model; the role of amyloid,
tau protein and metals; to oxidative stress. The present issue
reports nine articles addressing the most exciting and relevant
topics in the field of AD. Two papers discuss interactions
of the amyloid beta peptide (Aβ)/Aβ
precursor protein (APP) with other cellular systems, two papers
highlight studies on anticho-linesterase (AChE) inhibitors,
one paper each presents studies on tau protein phosporylation,
apolipoprotein E (APOE) genotype, mild cognitive impairment
(MCI) and a promising treatment strategy. In addition, there
is an interesting ‘Commentary’ on angiotensin
converting Enzyme (ACE) inhibitor.
Standridge presents (p 95-108) a comprehensive view of the
neuropathophysiological mechanisms for AD, involving several
vicious cycles. A number of interactive systems that each
alone or together, once set in motion, amplify their own processes,
thereby accelerating the development of AD. Hypoperfusion,
the defective clearance of amyloid, and resultant increase
in amyloid deposition represent an example of vicious cycle.
In addition, AD symptoms most likely result from aberrant
nerve cell signaling and synaptic failure rather than nerve
cell death, which follows and accelerates the initial pathology
of AD. Heese and Akatsu summarize (p 109-121) both physiological
and pathophysiological functions of APP and its cleavage product
Aβ,
based on recent data from genomics, proteomics and molecular
genetics. This review provides an insight into interaction
of APP and Aβ
with other cellular systems present and their roles in the
pathogenesis of AD.
In addition to Aβ
deposition, AD is characterized by the presence of paired
helical filaments, mostly made up of hyperphosphorylated tau
protein. However, the mechanism for tau phosphorylation and
its interaction with metals are poorly understood and is an
active field of current research. One of the important kinases
that modifies tau protein is called GSK3. Herein, Gómez-Ramos
and colleagues (p 123-127) discuss the effect of two metals,
lithium and tungstate, on GSK3 (or tau I kinase) activity,
and its important implications for AD.
Mechanistic studies lead to the development of potential treatment
strategies. This is important because currently available
drugs transiently relieve some symptoms of AD but have no
significant effects on the progression of the disease. Based
on the prevailing “amyloid” hypothesis, preventing
the formation of “bioactive” Aβ
or inactivating previously formed bioactive Aβ
is becoming a promising approach for treating AD. Liu and
Schubert (p 129-135) describe a cell-based assay for detecting
bio-active Aβ
to screen for drugs that can inactivate bioactive Aβ
They discuss several promising compounds that can inactivate
bioactive Aβ
species, and this constitutes a promising approach for the
potential treatment of AD.
Research on currently available and FDA approved AChE inhibitor
drugs reveal interesting results. Doganay and colleagues report
(p 137-145) pharmacological manipulation of the vasoconstrictive
effects of Aβ
peptides by donepezil and rivastigmine. They postulate that
such AChE inhibitor drugs mediate these vascular modulatory
effects via an action on Aβ-mediated
vasoconstrictor mechanisms rather than an independent action
on endothelial or smooth muscle cell mediated responses. At
the clinical level, Behl and colleagues determined if there
are differential treatment effects of second-generation AChE
inhibitors over one year. They report (p 147-156) that cholinesterase
inhibitors slow decline in executive functions, rather than
memory in AD based on this observational study. Notably, executive,
language and visuospatial functions, rather than memory, seems
to be more amenable to stabilization over one year by cholinesterase
inhibitors in AD.
In the area of genetic risk factors for AD, Sabbagh and colleagues
report (p 157-160) studies on the effect of the APOE genotype
on the lipid profile in AD. They report that APOE gene status
has minimal influence on either the lipid panel or mean age
of onset for AD. Interestingly, APOE gene dose influences
the lipid panel with APOE ε2/2,
and ε2/3
having significantly better lipid panels and later age of
onset. In the area of predictors for AD, current research
suggests that half of MCI patients convert to dementia within
3 years. Since not all patients convert to dementia it is
useful to find reliable predictors, which would help start
the appropriate treatment at the early stage. Modrego discusses
(p 161-170) various potential predictors, such as CSF biomarkers
(Aβ,
tau protein), hippocampal atrophy (MRI), proton MRS and APOE
genotype. The author suggests that a combined use of cognitive
tests, APOE genotype, and a neuroradiological technique such
as MRI or MRS is probably the best instrument for prediction
purposes. Finally, Kehoe and Wil-cock write (p 171-173) a
“Commentary” highlighting current clinical and
biological dichotomy on the renin angiotensin system in AD.
Also they propose an “out of the box” approach:
RAAS modifying treatments, such as an-giotensin receptor blockers,
that fail to influence Aβ
degrading enzymes, may offer a useful alternative
should ACE inhibitor be detrimental to AD pathology.
Thus, the present issue of Current Alzheimer Research
updates a sample of vast research from the molecular bases
of the disease to potential drug targets to therapeutic strategies
for AD. These articles also represent various contemporary
cellular, genetic, and in vivo models to study AD.
In addition, this issue reports studies from clinical drug
trials. We hope that by reporting cutting edge studies on
AD and providing an insightful summary of important advances
in AD research, potential drug development strategies will
eventually emerge.
I am pleased to announce that the journal Current Alzheimer
Research will be indexed in PsycINFO in addition
to its current listing in the Alzheimer Research Forum, Current
Contents and the PubMed/MEDLINE databases. The Bentham
Science Publisher has agreed to continue to provide online
Abstracts of the articles, which are freely available on the
journal’s website (http://www. bentham.org/car/). Finally,
I seek comments from you about the articles published in this
journal, and also request review papers and original reports
from your research.
Debomoy K. Lahiri
Editor-in-Chief
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]
Vicious Cycles Within the Neuropathophysiologic Mechanisms
of Alzheimer’s Disease
John B. Standridge
Rigorous scientific research has identified multiple interactive
mechanisms that parallel and are likely causative of the development
of Alzheimer’s disease (AD). Causative mechanisms include
genomics, the creation of amyloid beta (Abeta), factors inhibiting
the Abeta removal process, the transformation of Abeta to
its toxic forms (various forms of Abeta aggregation), and
lastly the oxidative, inflammatory, and other effects of toxic
Abeta. Fibrillar beta-amyloid peptide, a major component of
senile plaques in AD brain, is known to induce microglial-mediated
neurotoxicity under certain conditions, but some recent studies
support the notion that Abeta oligomers are the primary neurotoxins.
Abeta-42 oligomers that are soluble and highly neurotoxic,
referred to as Abeta-derived diffusible ligands (ADDLs), assemble
under conditions that block fibril formation. These oligomers
bind to dendrite surfaces in small clusters with ligand-like
specificity and are capable of destroying hippocampal neurons
at nanomolar concentrations. Evidence is presented that AD
is triggered by these soluble, neurotoxic assemblies of Abeta
rather than the late stage pathology landmarks of amyloid
plaques and tangles. The premise is that AD symptoms stem
from aberrant nerve cell signaling and synaptic failure rather
than nerve cell death, which nevertheless follows and exacerbates
the initial pathologies of AD.
The defective clearance of amyloid leads to amyloid angiopathy
that in turn perpetuates hypoperfusion that affects formation
as well as absorption of CSF thereby altering clearance of
amyloid and promoting vascular and parenchymal deposition[1].
Hypoperfusion, the defective clearance of amyloid, and resultant
increase in amyloid deposition thus represent a vicious cycle.
Chronic vascular hypoperfusion-induced mitochondrial failure
results in oxidative damage, which drives caspase 3-mediated
Abeta peptide secretion and enhances amyloidogenic APP processing.
Intracellular Abeta accumulation in turn promotes a significant
oxidative and inflammatory mechanism that generates a vicious
cycle of Abeta generation and oxidation, each accelerating
the other. Abeta activates astrocytes that add to the oxidative
imbalance, upregulate the expression of APP via TGF-beta,
and are capable of expressing BACE1. Each of these 3 actions
accelerates the larger cycle of cholinergic neuron destruction.
As oxidative stress induces lesions of cholinergic nuclei
producing a reduction in cholinergic neurotransmission, a
subsequent increase in cortical APP involving PKCepsilon leads
to accelerated amyloidogenic APP metabolism. The linkage of
cholinergic activation and APP metabolism completes an additional
feedback loop wherein the damage wrought by Abeta accelerates
further Abeta production.
A comprehensive vision of the neuropathophysiologic mechanisms
that result in AD reveals several vicious cycles within a
larger vicious cycle, that is to say, a number of interactive
systems that each, once set in motion, amplify their own processes,
thus accelerating the development of AD.
[Back to top]
Alzheimer’s Disease – An Interactive Perspective
Klaus Heese and Hiroyasu Akatsua
Alzheimer's disease (AD) is an age-related neurodegenerative
disorder that is characterized by a progressive loss in memory
and deterioration of the higher cognitive functions. The brain
of an individual with AD exhibits extracellular senile plaques
of aggregated amyloid-beta-peptide (Aβ
), intracellular neurofibrillary tangles (NFTs) that
consist of hyperphosphorylated tau protein (P-tau) and a profound
loss of basal forebrain cholinergic neurons that innervate
the hippocampus and the neocortex. Recent data obtained via
genomics, proteomics and molecular genetics, have gleaned
new information with regard to the physiological and pathophysiological
functions of the amyloid precursor protein (APP) and its cleavage
product Aβ
. This review glances over several aspects that may
play a major role in the pathogenesis of AD providing an insight
into APP’s and Aβ
’s interplay with other cellular systems.
[Back to top]
Inhibition of GSK3 Dependent Tau Phosphorylation by
Metals
Alberto Gómez-Ramos, Jorge Domínguez,
Delia Zafra, Helena Corominola, Ramon Gomis, Joan J. Guinovart
and Jesús Avila
One of the main pathological characteristics of Alzheimer’s
disease is the presence in the brain of the patients of an
aberrant structure, the paired helical filaments, composed
of hyperphosphorylated tau. The level of tau phosphorylation
has been correlated with the capacity for tau aggregation.
Thus, the mechanism for tau phosphorylation could be important
to clarify those pathological features in Alzheimer’s
disease.
Tau protein could be modified by different kinases, being
GSK3 the one that could modify more sites of that protein.
GSK3 activity could be modulate by the presence of metals
like magnesium that can be required for the proper function
of the kinase, whereas, metals like manganesum or lithium
inhibit the activity of the kinase. Many works have been done
to study the inhibition of GSK3 by lithium, a specific inhibitor
of that kinase. More recently, it has been indicated that
sodium tungstate could also inhibit GSK3 through a different
mechanism. In this review, we discuss the effect of these
two metals, lithium and tungstate, on GSK3 (or tau I kinase)
activity.
[Back to top]
Treating Alzheimer’s Disease by Inactivating
Bioactive Amyloid β
Peptide
Yuanbin Liu and David Schubert
Treating Alzheimer’s disease (AD) is one of today’s
biggest unmet medical needs. The drugs currently available
transiently relieve some symptoms but have no significant
effects on the progression of the disease. Progress in the
past decade suggests that the amyloidogenesis of the inactive
monomeric amyloid β
peptide (Aβ
) into a subset of toxic Aβ
polymers is responsible for neurodegeneration in AD.
Not all forms of Aβ
aggregates are damaging, for there are patients whose
brains accumulated large amounts of Aβ
in the form of plaques, but they had no obvious neurodegeneration
and symptoms of dementia. Since Aβ
can polymerize into many types of polymers or aggregates,
the form of Aβ
that induces neurodegeneration in AD, defined here
as bioactive Aβ
, is not clear. Preventing the formation of bioactive
Aβ
or inactivating previously formed bioactive Aβ
is a promising approach for treating AD. This review
describes our efforts to develop a cell-based assay for detecting
bioactive Aβ
, to verify the concept of bioactive Aβ
in an animal model of AD and in post mortem brain
tissue from AD patients, and to use this assay to screen for
drugs that can inactivate bioactive Aβ
. These studies show the proof in principle that inactivating
bioactive Aβ
is a promising approach to treat AD. Several promising
compounds that can inactivate bioactive Aβ
species are also described.
[Back to top]
Pharmacological Manipulation of the Vasoconstrictive
Effects of Amyloid-β
Peptides by Donepezil and Rivastigmine
Goksel Doganay, Bereha Khodr, George Georgiou
and Zeinab Khalil
The amyloid-β
(Aβ
peptide has been linked to the pathology of Alzheimer’s
disease (AD). There is now evidence to support a vasoconstrictive
effect of Aβ
protein that could be detected in peripheral skin
microvasculature. In this study we investigated the ability
of acetylcholinesterase (AChE) inhibitors, Donepezil and Rivastigmine,
to modulate the vasoconstrictor activity of Aβ
25-35
and Aβ
1-40.
The ability of these drugs to improve endothelial mediated
vascular responses to acetylcholine and bradykinin subsequent
to perfusion of Aβ
peptides was also investigated. The vascular responses to
Aβ
peptides, acetylcholine, bradykinin and sodium nitroprusside
and their modulation by acetylcholinesterase inhibitors were
examined in the base of a vacuum induced blister raised on
the rat hind footpad using laser Doppler flowmetry. Aβ25-35
(1μM)
and Aβ1-40
(0.1μM)
induced a vasoconstrictor effect and significantly reduced
the vasodilator response to acetylcholine (100μM)
and bradykinin (1μM).
Donepezil (100μM)
and Rivastigmine (100μM)
both reduced the vasoconstrictor effect of Aβ
peptides, and significantly restored the endothelial vascular
response to acetylcholine. Similarly, Donepezil significantly
restored the endothelial vascular response to bradykinin.
The results also showed that the actions of acetylcholinesterase
inhibitors are independent of a direct action on smooth muscle
cell reactivity or on endothelial cell function in the absence
of Aβ.
The current study provides the first evidence in vivo
to suggest that acetylcholinesterase inhibitors modulate the
vasoconstrictive effects of Aβ
peptides at the level of skin microvasculature. We raise the
notion that Donepezil and Rivastigmine mediate these vascular
modulatory effects via an action on Aβ-mediated
vasoconstrictor mechanisms rather than an independent action
on endothelial or smooth muscle cell mediated responses.
[Back to top]
Cholinesterase Inhibitors Slow Decline in Executive
Functions, Rather than Memory, in Alzheimer’s Disease:
A 1-Year Observational Study in the Sunnybrook Dementia Cohort
Pearl Behl, Krista L. Lanctôt, David
L. Streiner, Isabelle Guimont and Sandra E. Black
To determine if there are differential treatment effects
of second-generation cholinesterase inhibitors over one year,
130 patients (untreated=65, treated=65) meeting NINCDS-ADRDA
criteria for mild or moderate probable AD underwent standardized
cognitive testing at baseline and 12 months later at a university
memory clinic. Patients were followed either prior to or after
the availability of treatment and were matched on education
and baseline Mini Mental State Examination (MMSE). A detailed
medical history evaluation was conducted. In this well matched
longitudinal observational cohort study, there were no differences
in the prevalence of comorbid illnesses, concomitant medication
use or vascular risk factors except for a greater number of
treated patients with a previous history of smoking. Separate
repeated measures MANCOVAs on the MMSE, Mattis Dementia Rating
Scale (DRS), and its 5 subscores (attention, initiation/perseveration,
conceptualization, construction and memory) (Bonferroni corrected),
after covarying for the effects of smoking, and SSRI use,
showed less decline over one year in the treated group in
overall cognition and in all subscores of the DRS except for
memory (effect sizes 0.5-0.7). Less decline was also seen
in the treated group in function and in instrumental and basic
activities of daily living as measured with the Disability
Assessment for Dementia Scale (DAD) (effect sizes 0.4-0.8).
Executive, language and visuospatial functions, rather than
memory, appeared to be more amenable to stabilization over
one year by cholinesterase inhibitors in AD.
[Back to top]
Studies on the Effect of the Apolipoprotein E Genotype
on the Lipid Profile in Alzheimer’s Disease
Marwan N. Sabbagh, Shawn Sandhu, Heather Kolody,
Tyson Lahti, Nina B. Silverberg and D. Larry Sparks
Objective: To determine whether Apolipoprotein
E4 (Apo E4) gene status or ApoE gene dose affect the lipid
profile in AD.
Background: Links between hypercholesterolemia and AD development
continue to grow. Presently, limited information exists about
the influence of the Apo E genotype on the lipid profile characteristics
in AD.
Methods: We examined the lipid profiles (total cholesterol
(TC), high-density lipoprotein (HDL), lower-density lipopro-tein
(LDL), TC/HDL ratio, and triglyceride (TG) levels) of 142
subjects with probable or possible AD (mean age 76.5 ±
8.9 years), not on lipid lowering therapy by Apo E
genotype. Assessment was done by gene status and gene dose.
Results: ApoE4 gene status did not reveal any significant
differences in the lipid profile except for LDL. However,
significant differences were observed by ApoE gene dose.
Conclusion: ApoE gene status has minimal influence
on the lipid panel or mean age in AD. Apo E gene dose does
influence the lipid panel with Apo E 2/2, and 2/3 having significantly
better lipid panels and older age of onset.
[Back to top]
Predictors of Conversion to Dementia of Probable Alzheimer
Type in Patients with Mild Cognitive Impairment
Pedro J. Modrego
BACKGROUND. Mild Cognitive Impairment is a common condition
defined as transitional state between normality and dementia
of Alzheimer type. Clinically is characterized by subjective
and objective memory loss beyond the expected for age and
educational level, although a broad range of cognitive inefficiencies
may appear, with preservation of daily living activities.
Approximately half the patients convert to dementia within
3 years. Since no all patients convert to dementia it is essential
to find reliable predictors so as to start the appropriate
treatment as soon as possible.
METHOD. Extensive Medline-based search for articles dealing
with predictors of conversion to dementia in Mild Cognitive
Impairment (MCI).
RESULTS. There is a substantial body of literature dealing
with predictors of dementia in patients with MCI. These pre-dictors
range from a simple delayed recall task on Mini-Mental to
sophisticated radiological techniques and CSF bio-markers.
Comprehensive neuropsychological tests rarely surpass 70%
sensitivity and specificity. The presence of the APOE epsilon
4 allele has been associated with increased risk of conversion
but the sensitivity is quite low. CSF bio-chemical markers
are being developed with encouraging results. β
-amyloid 42 protein is usually lower in converters
than in people with stable cognitive status and tau protein
is higher. The sensitivity is substantial but specificity
is so far low. An epitope of tau protein (P231) looks more
specific of Alzheimer’s disease and therefore a promising
biomarker. In the blood, high β
-amyloid protein levels indicate risk of conversion
but only a few studies have been published. Hippocampal or
entorhinal atrophy on MRI is one of the most used radiological
markers of conversion but quantification of atrophy is not
simple as it is subject to artifacts and anatomic variations.
Proton Magnetic Resonance Spectroscopy (MRS) and Positron
Emission Tomography (PET) are emerging as the most promising
predictive tools. The highest degree of accuracy (>90%)
has been achieved by means of PET plus either memory performance
or APOE4 genotype. However, the samples of the published studies
are mostly small, and these instruments are not widely available.
CONCLUSIONS. There is no enough evidence to recommend specific
techniques for predictions. Until an accurate marker is developed,
a combined use of cognitive tests, APOE genotype, and a neuroradiological
technique is probably the best option for prediction purposes
depending on availability and experience.
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