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Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer
Research
Volume 5, Number 5, October 2008
Contents
Fatty Aspirin: A New Perspective in
the Prevention of Dementia of Alzheimer’s Type? Pp.
422-431
M. Pomponi, A. Di Gioia, P. Bria and
M.F.L. Pomponi
[Abstract]
Evidence for Altered LRP/RAGE
Expression in Alzheimer Lesion Pathogenesis Pp.
432-437
B. Jeynes and J. Provias
[Abstract]
Insulin Resistance and
Alzheimer´s Disease: Molecular Links & Clinical
Implications Pp. 438-447
K.F. Neumann, L. Rojo, L.P. Navarrete, G.
Farías, P. Reyes and R.B. Maccioni
[Abstract]
The Cholesterol Transport
Inhibitor U18666a Regulates Amyloid Precursor Protein Metabolism
and Trafficking in N2aAPP “Swedish” Cells
Pp. 448-456
W. Davis Jr.
[Abstract]
Mitochondria, Mitochondrial
DNA and Alzheimer's Disease. What Comes First? Pp.
457-468
M. Mancuso, D. Orsucci, G. Siciliano and
L. Murri
[Abstract]
Increased Aβ1-42
Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity
Pp. 469-474
S.M. Chafekar, R. Zwart, R. Veerhuis, H.
Vanderstichele, F. Baas and W. Scheper
[Abstract]
Relevance of Aβ1-42
Intrahippocampal Injection as An Animal Model of Inflamed
Alzheimer’s Disease Brain Pp. 475-480
J.G. McLarnon and J.K. Ryu
[Abstract]
Auto-Contractive Maps:
An Artificial Adaptive System for Data Mining. An Application
to Alzheimer Disease 481-498
M. Buscema, E. Grossi, D. Snowdon and
P. Antuono
[Abstract]
Abstracts
[Back to top]
Fatty Aspirin: A New Perspective
in the Prevention of Dementia of Alzheimer’s Type?
M. Pomponi, A. Di Gioia, P. Bria and M.F.L. Pomponi
Alzheimer’s disease (AD) leads to a dramatic decline
in cognitive abilities and memory. A more modest disruption
of memory often occurs in normal aging and the same circuits
that are devastated through degeneration in AD are vulnerable
to sub-lethal age-related changes that alter synaptic transmission.
There are numerous indications that aberrant plasticity is
critically involved in Alzheimer’s. Is ageing itself
the major risk factor for AD? Is AD an acceleration of normal
ageing? We assume that the ability of the brain is to modify
its own structural organization and functioning which is liable
to become impaired in ageing until it becomes dramatically
impaired in Alzheimer’s. Moreover, ageing can compromise
the conversion of dietary alpha-linolenic acid (ALA) to docosahexaenoic
acid (DHA). DHA regulates synaptogenesis and affects the synaptic
structure, and synapse density is reduced in ageing. DHA and
newly identified DHA-derived messenger, neuroprotecting D1
(NPD1), protect synapses and decrease the number of activated
microglia in the hippocampal system. Delaying AD onset by
a few years would reduce the number of the cases of dementia
in the community. DHA (and NPD1?) and aspirin induce brain-derived
neurotrophic factor (BDNF) protein expression and this protein
has a crucial role in neuronal survival. The authors –
in view of the increased neuroinflammatory reaction frequently
observed during normal brain ageing - suggest the long-term
use of “fatty aspirin”, an association of DHA
and/or NPD1 and aspirin (or nitroaspirin), to postpone, or
prevent, the structural neurodegeneration of the brain.
[Back to top]
Evidence for Altered LRP/RAGE Expression in Alzheimer Lesion
Pathogenesis
B. Jeynes and J. Provias
There is significant evidence to suggest that a damaged
or dysfunctional blood-brain barrier (BBB) may contribute
to the pathogenesis of Alzheimer’s disease (AD) lesions.
Lipoprotein receptor-related protein (LRP-1) and receptor
for advanced glycation end products (RAGE) are known to be
important (BBB) capillary transport proteins. Altered expression
of either of these capillary endothelial LRP-1 and RAGE receptor
proteins could indicate a dysfunction of the BBB and its transport
regulation of beta-amyloid (Aβ).
Cortical samples from the superior temporal (ST) and calcarine
occipital (COC) cortices of ten confirmed AD brains and ten
comparison group (CG) brains were examined. The densities
of neurofibrillary tangles (NFTs), senile plaques (SPs) and
LRP-1 and RAGE positive capillaries were recorded and statistically
analyzed. There was a statistically significant difference
between AD and CG cases and the densities of LRP-1 and RAGE
positive capillaries, the AD cases demonstrating the greater
numbers. Further, in AD brains there were significant negative
correlations between the Aβ
burden of SPs and both LRP-1 and RAGE-positive capillaries
[p<.001].
Additionally, there was a strong positive correlation between
LRP-1 and RAGE capillaries in AD brains [p<.001].
These results suggest that alterations in the LRP-1 and RAGE
mediated transport of Aβ
take place in AD brains in lesion prone regions and may therefore
contribute to SP lesion pathogenesis.
[Back to top]
Insulin Resistance and Alzheimer´s Disease: Molecular
Links & Clinical Implications
K.F. Neumann, L. Rojo, L.P. Navarrete, G. Farías,
P. Reyes and R.B. Maccioni
Hyperinsulinemia as well as type II diabetes mellitus
are among the risk factors for Alzheimer´s disease (AD).
However, the molecular and cellular basis that link insulin
resistance disorders and diabetes with AD are far from clear.
Here, we discuss the potential molecular mechanisms that may
explain the participation of these metabolic disorders in
the pathogenesis of AD. The human brain uses glucose as a
primary fuel; insulin secreted by the pancreas cross the blood-brain
barrier (BBB), reaching neurons and glial cells, and exerts
a region-specific effect on glucose metabolism. Glucose homeostasis
is critical for energy generation, neuronal maintenance, neurogenesis,
neurotransmitter regulation, cell survival and synaptic plasticity.
It also plays a key role in cognitive function. In an insulin
resistance condition, there is a reduced sensitivity to insulin
resulting in hyperinsulinemia; this condition persists for
several years before becoming fullblown diabetes. Toxic levels
of insulin negatively influence neuronal function and survival,
and elevation of peripheral insulin concentration acutely
increases its cerebrospinal fluid (CSF) concentration. Peripheral
hyperinsulinemia correlates with an abnormal removal of the
amyloid beta peptide (Aβ)
and an increase of tau hyperphosphorylation as a result of
augmented cdk5 and GSK3β
activities. This leads to cellular cascades that trigger a
neurodegenerative phenotype and decline in cognitive function.
Chronic peripheral hyperinsulinemia results in a reduction
of insulin transport across the BBB and a reduced insulin
signaling in brain, altering all of insulin’s actions,
including its anti-apoptotic effect. However, the increase
in brain insulin levels resulting from its peripheral administration
at optimal doses has shown a cognitionenhancing effect in
patient with AD. Some drugs utilized in type II diabetes mellitus
reduce cognitive impairment associated with AD. The link between
insulin resistance and neurodegeneration and AD, and the possible
therapeutic targets in preventing the insulin-resistance disorders
are analyzed.
[Back to top]
The Cholesterol Transport Inhibitor U18666a Regulates Amyloid
Precursor Protein Metabolism and Trafficking in N2aAPP “Swedish”
Cells
W. Davis Jr.
Cholesterol transport is a key regulator of amyloid precursor
protein (APP) processing and β-amyloid
(Aβ)
production, implicated in Alzheimer’s disease. Perturbation
of cholesterol transport can be pharmacologically induced
by the class II amphiphile 3-β-[2-(diethylamino)ethoxy]androst-5-en-17-one,
U18666a; however, the mechanisms by which U18666a controls
APP metabolism and trafficking have not been elucidated. We
proposed to determine how U18666a regulates APP holoprotein
metabolism and trafficking in N2a mouse neuroblastoma cells
stably expressing the human APP protein. Secretion of Aβ1-40
was reduced in U18666a-treated cells. U18666a elevated the
steady state level of the APP holoprotein but not APP mRNA
levels. U18666a increased sAPPα
secretion and intracellular α-CTF/C83
levels but intracellular βCTF/C99
levels were reduced. The increase in APP protein level was
due to decreased catabolism rather than increased APP synthesis.
Interestingly, U18666a regulated APP trafficking and increased
the level of the holoprotein at the cell surface for α-secretase
processing and reduced internalization for β-secretase
processing. These data demonstrate that U18666a effects on
cholesterol transport function to regulate amyloid precursor
protein metabolism and trafficking.
[Back to top]
Mitochondria, Mitochondrial DNA and Alzheimer's Disease. What
Comes First?
M. Mancuso, D. Orsucci, G. Siciliano and L. Murri
To date, the beta amyloid (Aβ)
cascade hypothesis remains the main pathogenetic model of
Alzheimer’s disease (AD), but its role in the majority
of sporadic AD cases is unclear. The mitochondria play central
role in the bioenergetics of the cell and apoptotic cell death.
In the past 20 years research has been directed at clarifying
the involvement of mitochondria and defects in mitochondrial
oxidative phosphorylation in late-onset neurodegenerative
disorders, including AD. Morphological, biochemical and genetic
abnormalities of the mitochondria in several AD tissues have
been reported. Impaired mitochondrial respiration, particularly
COX deficiency, has been observed in brain, platelets and
fibroblasts of AD patients. The “mitochondrial cascade
hypothesis” could explain many of the biochemical, genetic
and pathological features of sporadic AD. Somatic mutations
in mitochondrial DNA (mtDNA) could cause energy failure, increased
oxidative stress and accumulation of Aβ,
which in a vicious cycle reinforces the mtDNA damage and the
oxidative stress. Despite the evidence of mitochondrial dysfunction
in AD, no causative mutations in the mtDNA have been detected
so far. Indeed, results of studies on the role of mtDNA haplogroups
in AD are controversial. In this review we discuss the role
of the mitochondria in the cascade of events leading to AD,
and we will try to provide an answer to the question “what
comes first”.
[Back to top]
Increased Aβ1-42
Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity
S.M. Chafekar, R. Zwart, R. Veerhuis, H. Vanderstichele,
F. Baas and
W. Scheper
Alzheimer’s disease (AD) is characterized by the
aggregation and subsequent deposition of misfolded β-amyloid
(Aβ)
peptide. The unfolded protein response (UPR) is activated
by misfolded protein stress in the endoplasmic reticulum (ER).
In previous studies we demonstrated mild activation of the
UPR by extracellularly applied oligomeric but not fibrillar
Aβ1-42.
In addition, we showed that oligomeric Aβ1-42
is internalized by cells, whereas fibrillar Aβ1-42
remains on the outside of the cell. Inhibition of Aβ
uptake specifically inhibits toxicity of Aβ1-42
oligomers, underscoring the toxic potential of intracellular
Aβ.
Therefore, in the present study, we investigated the connection
between intracellularly produced Aβ
and the ER stress response, using human neuroblastoma cells
overexpressing either wild type APP695 (APPwt) or APP695V717F
(APPmut). Both cell lines secrete higher levels of Aβ1-40
and Aβ1-42
compared to the parental line. In addition, APPmut produces
more Aβ1-42
than APPwt. Whereas the basal levels of UPR markers are not
different, we find augmented UPR induction in response to
ER stress in both APP overproducing cell lines compared to
the parental cell line, with the strongest UPR activation
in APPmut cells. In addition, ER stress toxicity was highest
in APPmut cells, strongly suggesting a connection with the
production of Aβ1-42.
The difference in ER stress mediated toxicity between the
APPwt and APPmut cell lines is alleviated by pretreatment
with γ-secretase
inhibitor, indicating that it is dependent on Aβ
production and in particular on Aβ1-42.
Our data indicate that increased Aβ1-42
production sensitizes neuroblastoma cells for ER stress toxicity.
[Back to top]
Relevance of Aβ1-42
Intrahippocampal Injection as An Animal Model of Inflamed
Alzheimer’s Disease Brain
J.G. McLarnon and J.K. Ryu
Injection of amyloid-beta peptide (Aβ1-42)
into hippocampal and cortical regions of brain may have utility
as an animal model of Alzheimer’s disease (AD) emphasizing
the inflammatory component of disease pathology. This review
summarizes recent evidence supporting the relevance of the
peptide injection model to describe inflammatory conditions
in AD brain. A wide spectrum of responses are considered from
effects of Aβ1-42
on animal behavior and cognitive performance to peptide actions
at the cellular and molecular levels. In the latter case a
particular focus is placed on inflammatory responses mediated
by activated microglia. Specific pharmacological modulations
of microglial signaling pathways and factors and how they
shape patterns of inflammatory reactivity in peptide-injected
brain are included. Overall, the considerations for the validity
and limitations of Aβ1-42
injection as an animal model for AD pathology are also discussed.
[Back to top]
Auto-Contractive Maps: An Artificial Adaptive System for Data
Mining. An Application to Alzheimer Disease
M. Buscema, E. Grossi, D. Snowdon and P. Antuono
This article presents a new paradigm of Artificial Neural
Networks (ANNs): the Auto-Contractive Maps (Auto-CM). The
Auto-CM differ from the traditional ANNs under many viewpoints:
the Auto-CM start their learning task without a random initialization
of their weights, they meet their convergence criterion when
all their output nodes become null, their weights matrix develops
a data driven warping of the original Euclidean space, they
show suitable topological properties, etc. Further two new
algorithms, theoretically linked to Auto-CM are presented:
the first one is useful to evaluate the complexity and the
topological information of any kind of connected graph: the
H Function is the index to measure the global hubness of the
graph generated by the Auto-CM weights matrix. The second
one is named Maximally Regular Graph (MRG) and it is an development
of the traditionally Minimum Spanning Tree (MST). Finally,
Auto-CM and MRG, with the support of the H Function, are applied
to a real complex dataset about Alzheimer disease: this data
come from the very known Nuns Study, where variables measuring
the abilities of normal and Alzheimer subject during their
lifespan and variables measuring the number of the plaques
and of the tangles in their brain after their death.
The example of the Alzheimer data base is extremely useful
to figure out how this new approach can help to re design
bot-tom-up the overall structure of factors related to a complex
disease like this.
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