| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 5, Number 1, February 2008
Contents
Editorial: Progress of ‘Current
Alzheimer Research’ and Update on Roles of Lipids, Estrogen,
Neurotrophins and Cytokines in Alzheimer’s Disease
Pp. 1-3
Debomoy K. Lahiri
Lipids as Key Players in Alzheimer’s
Disease - Alterations in Metabolism and Genetics
Pp. 4-14
Ferhan Girgin Sagin and Eser Yildirim Sozmen
[Abstract]
Functional Role of Lipoprotein Receptors in Alzheimer’s
Disease Pp. 15-25
Sebastian Jaeger and Claus U. Pietrzik
[Abstract]
Detoxification Depot for β-Amyloid
Peptides Pp. 26-32
Ranjini K. Sundaram, Chinnaswamy Kasinathan, Stanley Stein
and Pazhani Sundaram
[Abstract]
Pro-inflammatory Cytokines Modulate Glial Apolipoprotein
E Secretion Pp. 33-37
Rosanne Aleong, Jean-Francois Blain and Judes Poirier
[Abstract]
Neurotrophins - From Pathophysiology to Treatment
in Alzheimer’s Disease Pp. 38-44
Olaf Schulte-Herbrüggen, Maria C. Jockers-Scherübl
and Rainer Hellweg
[Abstract]
Levels of Estrogen Receptors α
and β
in Frontal Cortex of Patients with Alzheimer’s Disease:
Relationship to Mini Mental State Examination Scores Pp.
45-51
Jeremiah F. Kelly, Julia L. Bienias, Avni Shah, Kathleen
A. Meeke, Julie A. Schneider, Edwin Soriano and David A. Bennett
[Abstract]
Differentiating the Dementias. Revisiting Synucleinopathies
and Tauopathies Pp. 52-60
Catherine Hickey, Terry Chisholm, Michael J. Passmore,
Jonathon Darcy O’Brien and Jennifer Johnston
[Abstract]
Prevalence of Neuropsychiatric Symptoms in Alzheimer’s
Disease and Vascular Dementia Pp. 61-69
Manuel Fernández-Martínez, Jessica Castro,
Ana Molano, Juan José Zarranz Rosa Monica Rodrigo and
Rafael Ortega
[Abstract]
Risk Factors of Alzheimer’s Disease Among
Iranian Population Pp. 70-72
Mahshid Foroughan, Zia Ghaemmagham Farahani, Maryam Shariatpanahi,
Mehrak Vaezinejad, Ahmad Ali Akbari Kamerani and Mehrdad Sheikhvatan
[Abstract]
Rofecoxib in Patients with Mild Cognitive Impairment:
Further Analyses of Data from a Randomized, Double Blind,
Trial Pp. 73-82
Paul S. Aisen, Leon J. Thal, Steven H. Ferris, Christopher
Assaid, Michael L. Nessly, Michael J. Giuliani, Christopher
R. Lines, Barbara A. Norman and William Z. Potter
[Abstract]
Memantine Treatment in Patients with Mild to
Moderate Alzheimer’s Disease Already Receiving a Cholinesterase
Inhibitor: A Randomized, Double-Blind, Placeb Controlled Trial
Pp. 83-89
Anton P. Porsteinsson, George T. Grossberg,
Jacobo Mintzer and Jason T. Olin for the Memantine MEM-MD-12
Study Grou
[Abstract]
Abstracts
[Back to top]
Editorial:
Progress of ‘Current Alzheimer Research’ and Update
on Roles of Lipids, Estrogen, Neurotrophins and Cytokines
in Alzheimer’s Disease
Debomoy K. Lahiri
[Back to top]
Lipids as Key Players in Alzheimer’s Disease - Alterations
in Metabolism and Genetics
Ferhan Girgin Sagin and Eser Yildirim Sozmen
Advances in Alzheimer Disease (AD) research suggest that
central nervous system (CNS) lipids play a key role in the
pathogenesis. This role is attributed to the rich lipid content
of CNS structures and the presence of blood brain barrier
which disables the exchange of lipids between CNS and plasma.
Among these lipids, cholesterol is a unique molecule provided
mainly by its de novo synthesis in the CNS. Special apolipoproteins
used for its efficient recycling within the CNS and special
oxysterols formed that are specific to brain all contribute
to the unique properties of the molecule. Above all, the presence
of cholesterol in the membrane enables it to function as a
regulator of a number of protein related processes such as
the β-amyloid
precursor protein cleavage. Cholesterol reducing agents such
as statins are recently proposed to have a protective role
in AD. This review will focus on the role of cholesterol metabolism
and genetics in AD. Current literature investigating the relationship
between cholesterol and AD will be evaluated from the pathophysiological
perspective. Genetic studies concerning proteins which are
involved in the CNS cholesterol metabolism will also be summarized
in the hope that genomics may stimulate further studies and
thus contribute to a more clear understanding of the molecular
mechanisms in the pathophysiology of AD.
[Back to top]
Functional Role of Lipoprotein Receptors in Alzheimer’s
Disease
Sebastian Jaeger and Claus U. Pietrzik
The LDL receptor gene family constitutes a class of structurally
closely related cell surface receptors fulfilling diverse
functions in different organs, tissues, and cell types. The
LDL receptor is the prototype of this family, which also includes
the VLDLR, ApoER2/LRP8, LRP1 and LRP1B, as well as Megalin/GP330,
SorLA/LR11, LRP5, LRP6 and MEGF7. Recently several lines of
evidence have positioned the LDL receptor gene family as one
of the key players in Alzheimer’s disease (AD) research.
Initially this receptor family was of high interest due to
its key function in cholesterol/apolipoprotein E (ApoE) uptake,
with the ε4
allele of ApoE as the strongest genetic risk factor for late-onset
AD. It has been established that the cholesterol metabolism
of the cell has a strong impact on the production of Aβ,
the major component of the plaques found in the brain of AD-patients.
The original report that soluble amyloid precursor protein
(APP) containing the kunitz proteinase inhibitor (KPI) domain
might act as a ligand for LRP1 led to a complex investigation
of the interaction of both proteins and their potential function
in AD development. Meanwhile, it has been demonstrated that
LRP1 might bind to APP independent of the KPI domain in APP.
This APP – LRP1 interaction is facilitated through a
trimeric complex of APP-FE65-LRP1, which has a functional
role in APP processing. Along with LRP1, APP is transported
from the early secretory compartments to the cell surface
and subsequently internalised into the endosomal / lysosomal
compartments. Recent investigations indicate that ApoER2 and
SorLA fulfil a similar role in shifting APP localisation in
the cell, which affects APP processing and the production
of the APP derived amyloid β-peptide
(Aβ).
In addition to the effect of lipoprotein receptors on APP
processing and Aβ
production, LRP1 has been shown to bind Aβ
directly or indirectly through Aβ-lactoferrin,
Aβ-α2M
and Aβ-ApoE
complexes in vitro and in vivo. Based on
these observations two LRP1 mediated clearance mechanisms
of Aβ
are proposed to play a crucial role in the prevention of AD:
either Aβ-uptake
into a cell with its subsequent degradation or its transport
out of the brain over the blood brain barrier into the periphery.
Following this export Aβ
is degraded in the liver, where LRP1 potentially conducts
the removal of Aβ
from the blood stream.
Although the involvement of LDLR family members in AD is not
yet fully understood it becomes clear that they can directly
affect APP production, Aβ-clearance
and Aβ-transport
over the blood brain barrier.
[Back to top]
Detoxification Depot for β-Amyloid
Peptides
Ranjini K. Sundaram, Chinnaswamy Kasinathan, Stanley Stein
and Pazhani Sundaram
Alzheimer’s Disease (AD) is caused by the deposition
of insoluble and toxic amyloid peptides (Aβ)
in the brain leading to memory loss and other associated neurodegenerative
symptoms. To date there is limited treatment options and strategies
for treating AD. Studies have shown that clearance of the
amyloid plaques from the brain and thus from the blood could
be effective in stopping and or delaying the progression of
the disease. Small peptides derived from the Aβ-42
sequence, in particular KLVFF, have shown to be effective
binders of Aβ
peptides and thus could be useful in delaying progression
of the disease. We have taken advantage of this property by
generating the retro-inverso (RI) version of this peptide,
ffvlk, in different formats. We are presenting a new detox
gel system using poly ethylene glycol (PEG), polymerized and
cross linked with the RI peptides. We hypothesize that detox
gel incorporating RI peptides will act like a ‘sink’
to capture the Aβ
peptides from the surrounding environment. We tested these
detox gels for their ability to capture biotinylated Aβ-42
peptides in vitro. The results showed that the detox
gels bound Aβ-42
peptides effectively and irreversibly. Gels incorporating
the tetramer RI peptide exhibited maximum binding capacity.
The detox gel could be a potential candidate for treatment
strategies to deplete the brain of toxic amyloid peptides.
[Back to top]
Pro-inflammatory Cytokines Modulate Glial Apolipoprotein E
Secretion
Rosanne Aleong, Jean-Francois Blain and Judes Poirier
Alzheimer’s disease (AD) is a neurological disorder
characterized by plaques and an elevated immune response.
Specifically, increased expression of interleukin (IL)-1 and
tumour necrosis factor (TNF)-α
, has been observed in AD cerebrospinal fluid and temporal
brain tissue. Both of these immunomodulators were shown to
carry genetic variants that increase the risk of developing
AD. Studies have also established the apolipoprotein E (apoE)
gene to be a risk factor for AD with ε4
carriers having been found to show lower levels of brain apoE.
In the present study, treatment of primary rat mixed glial
cell cultures with IL-1β
induced a significant increase in extracellular apoE protein.
In contrast, treatment primary rat astrocyte and mixed glial
cell cultures with TNF-α
significantly reduced extracellular apoE protein levels. These
results are consistent with the notion that elevated cytokine
expression directly modulates immunosuppression and indirectly
apoE-mediated neuronal remodeling.
[Back to top]
Neurotrophins - From Pathophysiology to Treatment in Alzheimer’s
Disease
Olaf Schulte-Herbrüggen, Maria C. Jockers-Scherübl
and Rainer Hellweg
Alzheimer’s disease (AD) is the most common diagnosis
among dementia. As increasing longevity results in larger
numbers of AD patients and thus rising economic costs, there
has been intense research about the pathophysiology and treatment
strategies during the last years. Since neurotrophic factors
are not only responsible for neuronal development but also
critical for the maintenance of neurons, they represent mediators
of high interest within the research of neurodegeneration.
Thereby, NGF has been identified as a dynamic pattern during
the time course of neurodegeneration in AD. Post mortem studies
point to a lack of NGF action in early stages of AD. In contrast
NGF is found in enhanced concentrations in brains with severe
AD partly due to a pathologically altered axonal transport
of NGF in the neurons. Therefore, pharmacological interventions
starategies focus on an neurotrophin substitution in mild
to moderate cases of AD. Intensive research mostly in rodents
has recently led to first promising clinical trials of intracerebral
neurotrophin application pointing to a growing role of neurotrophins
in the establishment of new pharmacological strategies concerning
AD.
[Back to top]
Levels of Estrogen Receptors α
and β
in Frontal Cortex of Patients with Alzheimer’s Disease:
Relationship to Mini Mental State Examination Scores
Jeremiah F. Kelly, Julia L. Bienias, Avni Shah, Kathleen
A. Meeke, Julie A. Schneider, Edwin Soriano and David A. Bennett
Estrogen exerts beneficial effects on the brain throughout
life. Studies demonstrate that estrogen is neuroprotective
and that reduced brain estrogen activity may influence the
clinical course of Alzheimer’s disease (AD). Changes
in levels of estrogen receptors have been detected in postmortem
brain tissue of AD patients. Very little is known about the
relationship between clinical stage and levels of estrogen
receptors in postmortem brain. We hypothesized that estrogen
receptor levels would be related to severity of cognitive
impairment assessed proximate to death. Western blotting was
used to quantify ER-α
and ER-β
in nuclear, cytosolic, and crude membrane fractions of superior
frontal cortex from 25 AD patients. Multiple linear regression
analyses adjusted for age, sex, and education showed a significant
linear relationship between Mini-Mental State Examination
score (MMSE) and wild-type nuclear ER-α
(â =5.463, p = 0.03), but none between MMSE
and wild-type nuclear ER-β
(â = 2.29, p = 0.36). We incidentally observed additional
higher and lower molecular mass bands for ER-α
in study subjects. Additional experiments performed
on frontal cortex nuclear fractions prepared from subjects
enrolled in a different study confirmed that these same bands
are present in female and males with and without AD. Together
our data show a relationship between wild-type ER-α
and level of cognitive impairment in AD, and also
suggest the possibility that variant isoforms of ER-α
may be present in frontal cortex of patients with
and without AD.
[Back to top]
Differentiating the Dementias. Revisiting Synucleinopathies
and Tauopathies
Catherine Hickey, Terry Chisholm, Michael J. Passmore,
Jonathon Darcy O’Brien and Jennifer Johnston
Dementia is a common, chronic and progressive illness.
Many different types of dementia exist. It is important to
have knowledge of the various dementia presentations so that
the clinician can differentiate one type from another. Past
and current approaches of classifying dementias are reviewed
in this paper. The past cortical/subcortical scheme is reviewed
as well as the current synucleinopathy/tauopathy scheme. This
paper focuses on the most common synucleinopathies and tauopathies
including Alzheimer’s Dementia, Dementia with Lewy Bodies,
Parkinson’s Disease, Frontotemporal Dementia, Progressive
Supranuclear Palsy, Multiple System Atrophy and Corticobasal
Ganglionic Degeneration. We systematically approach each dementia
and review cognitive, psychiatry and neurological features
of each. We also compare and contrast each dementia and the
synucleinopathies and taupoathies alike. Our goal is to provide
the clinician with sufficient knowledge to competently and
confidently diagnose a patient who presents with progressive
cognitive decline and deterioration in functioning.
[Back to top]
Prevalence of Neuropsychiatric Symptoms in Alzheimer’s
Disease and Vascular Dementia
Manuel Fernández-Martínez, Jessica Castro,
Ana Molano, Juan José Zarranz Rosa Monica Rodrigo and
Rafael Ortega
Objetive: The study aimed to
describe the prevalence and severity of neuropsychiatric symptoms
in patients with Alzheimer’s disease (AD) and vascular
dementia (VaD).
Patients and methods: We prospectively
studied 65 patients with dementia, 37 met the criteria of
NINCDS-ADRDA for probable AD and 28 the clinical and radiological
criteria of NINDS-AIREN for VaD. Among VaD patients, 22 met
the ra-diological criteria for subcortical VaD. The Minimental
State Examination (MMSE) and the Neuropsychiatric Inventory
(NPI) were used to evaluate cognitive and neuropsychiatric
symptoms. All patients underwent a neuroimaging study (CTscan
and/or MRI). Patients were not treated with antidementia or
psychotropic drugs.
Results: Age, gender, educational
level and MMSE scores did not differ between patients (p >0.05).
The total prevalence of neuropsychiatric symptoms was similar
in both groups (AD94.6% vs. VaD 96.4%, p= 0.727). Sleep disturbances
(35.1% v 3.6%, p =0.002) and appetite changes (37.8% v 14.3%,
p = 0.032) were more prevalent in AD patients than in VaD
patients who met the NINDS-AIREN criteria. Sleep disturbances
(35.1% v 4.5%, p =0.008), appetite changes (37.8% v 13.6%,
p = 0.047) and aberrant motor behaviour (24.3% v 0%, p =0.012)
were more prevalent in AD patients than in subcortical VaD.
The total scores for sleep disturbance, appetite changes and
aberrant motor behavioural were higher in AD patients (p <
0.05).
Conclusions: There were no significant
differences between AD and VaD patients, except that sleep
disturbances, appetite changes and aberrant motor behaviour
that were more prevalent and severe in AD.
[Back to top]
Risk Factors of Alzheimer’s Disease Among Iranian Population
Mahshid Foroughan, Zia Ghaemmagham Farahani, Maryam Shariatpanahi,
Mehrak Vaezinejad, Ahmad Ali Akbari Kamerani and Mehrdad Sheikhvatan
Background: Several demographic,
environmental and clinical risk factors have been determined
as possible risk/protective factors of Alzheimer’s disease
(AD). The purpose of this study was to find out which one
of these known factors is related to developing of AD in Iranian
population. Materials and Methods:
In a case-control study, 115 elderly patients (mean age of
70±8.18 years) with DSM-IV based final diagnosis compared
with 115 non-demented counterparts matched for age ,sex, and
socioeconomic status regarding lifestyle, family history,
and history of bio-psychosocial health. Results:
All differences between the two groups were non-significant
except for history of hypertension (P=0.018) which was most
prevalent in AD group. Risk of the incident AD for the hypertensive
group was 1.71 (1.08-2.70) compared to the non-hypertensive
group.
Conclusion: These results confirm
the previously reported relationship between AD and vascular
factors. Prevention, early detection, and treatment of hypertension
may have some implications in the primary and secondary prevention
of AD.
[Back to top]
Rofecoxib in Patients with Mild Cognitive Impairment: Further
Analyses of Data from a Randomized, Double Blind, Trial
Paul S. Aisen, Leon J. Thal, Steven H. Ferris, Christopher
Assaid, Michael L. Nessly, Michael J. Giuliani, Christopher
R. Lines, Barbara A. Norman and William Z. Potter
A recent clinical trial in patients with Mild Cognitive
Impairment (MCI) found an increased rate of possible or probable
Alzheimer’s disease (AD) diagnoses in patients assigned
to rofecoxib compared to placebo. This unexpected finding
was difficult to interpret due to methodological issues and
a lack of confirmation on secondary endpoints, as well as
a lack of confirmation in trials in related populations. We
performed additional post hoc analyses to explore explanations
for the finding based on possible neuropathological, cardiovascular/cerebrovascular,
or cognitive effects of rofecoxib. 1) Neuropathological hypothesis:
Of the 189 incident cases of possible or probable AD, 154
were probable AD. In probable AD patients, the treatment hazard
ratio was reduced compared to the primary analysis –
a concordant finding would have strengthened a conclusion
that rofecoxib accelerated the underlying neuropathology of
AD. The treatment hazard ratio was increased in the remaining
35 patients with less certain diagnoses, but there was no
single predominant reason for the reduced certainty of diagnosis.
2) Cardiovascular hypothesis: Neither cardiovascular risk
status nor mean arterial blood pressure had an overall effect
on AD diagnosis or modified the treatment difference. 3) Cognitive
side-effects hypothesis: The percentages of patients with
non-specific NSAID-type central nervous system adverse events
were similar between the treatment groups. In summary, the
present analyses are limited by their post hoc nature but
provided little support for any of the possible explanations
explored. The significance of the observation that rofecoxib
increased the rate of conversion from MCI to AD remains uncertain.
[Back to top]
Memantine Treatment in Patients with Mild to Moderate Alzheimer’s
Disease Already Receiving a Cholinesterase Inhibitor: A Randomized,
Double-Blind, Placeb Controlled Trial
Anton P. Porsteinsson, George T. Grossberg,
Jacobo Mintzer and Jason T. Olin for the Memantine MEM-MD-12
Study Grou
Objective: To evaluate the efficacy
and safety of memantine in patients with mild to moderate
Alzheimer’s disease (AD) receiving cholinesterase inhibitor
(ChEI) treatment. Methods: Participants
(N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores
between 10-22 (inclusive), and concurrent stable use of ChEIs
(donepezil, rivastigmine, galantamine) were randomized to
placebo or memantine (20 mg once daily) for 24 weeks. Primary
outcomes were changes from baseline on the Alzheimer’s
Disease Assessment Scale-cognitive subscale (ADAS-cog) and
on Clinician’s Interview-Based Impression of Change
Plus Caregiver Input (CIBIC-Plus) score. Secondary measures
comprised the 23-item Alzheimer Disease Cooperative Study-Activities
of Daily Living Scale (ADCS-AD23),
Neuropsychiatric Inventory (NPI), and MMSE. Results:
At the end of the trial, there were no statistically significant
differences between the memantine- and placebo group on primary
and secondary outcome measures. The incidence of adverse events
(AEs) was similar between the two groups, with no AE occurring
in more than 5% of memantine-treated patients and at a rate
twice that of the placebo group. Conclusions:
In this trial, memantine did not show an advantage over placebo
based on protocol-specified primary or secondary analyses
in patients with mild to moderate AD on stable ChEI regimens.
There were no significant differences in tolerability and
safety between the memantine- and placebo groups.
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