| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 4, Number 2, April 2007
Contents
Exploring the Links between Obesity and Alzheimer’s
Disease
Guest Editor: Suzana S. Petanceska
Editorial
Exploring the Links between Obesity and Alzheimer’s
Disease Pp. 95-96
Suzana S. Petanceska
An Introduction to Obesity and Dementia Pp. 97-101
Elizabeth Barrett-Connor
[Abstract] [Purchase
Articles]
Body Mass Index in Midlife and Risk of Alzheimer Disease
and Vascular Dementia Pp. 103-109
Rachel A. Whitmer, Erica P. Gunderson, Charles P. Quesenberry
Jr, Jufen Zhou and Kristine Yaffe
[Abstract] [Purchase
Articles]
Relation of Obesity to Cognitive Function: Importance
of Central Obesity and Synergistic Influence of Concomitant
Hypertension. The Framingham Heart Study Pp. 111-116
Philip A. Wolf, Alexa Beiser, Merrill F. Elias, Rhoda
Au, Ramachandran S. Vasan and Sudha Seshadri
[Abstract] [Purchase
Articles]
The Epidemiology of Adiposity and Dementia
Pp. 117-122
Rachel A. Whitmer
[Abstract] [Purchase
Articles]
Metabolic Syndrome and Cognitive Decline
Pp. 123-126
Kristine Yaffe
[Abstract] [Purchase
Articles]
Adiposity and Alzheimer’s Disease Pp.
127-134
Jose A. Luchsinger and Richard Mayeux
[Abstract] [Purchase
Articles]
What Can Imaging Reveal about Obesity and the Brain?
Pp. 135-139
William Jagust
[Abstract] [Purchase
Articles]
Next Steps in Alzheimer’s Disease Research:
Interaction between Epidemiology and Basic Science
Pp. 141-143
Lenore J. Launer
[Abstract] [Purchase
Articles]
Animal Models of Obesity and Metabolic Syndrome: Potential
Tools for Alzheimer’s Disease Research Pp.
145-146
Kristin M. Abraham
[Abstract] [Purchase
Articles]
Insulin Resistance and Alzheimer’s Disease Pathogenesis:
Potential Mechanisms and Implications for Treatment
Pp. 147-152
Suzanne Craft
[Abstract] [Purchase
Articles]
Insulin Resistance, Glycemic Control and Adiposity:
Key Determinants of Healthy Lifespan Pp. 153-157
Peter S. DiStefano, Rory Curtis and Bradley J. Geddes
[Abstract] [Purchase
Articles]
Therapeutic Use of Agonists of the Nuclear Receptor
PPARγ
in Alzheimer’s Disease Pp. 159-164
Gary Landreth
[Abstract] [Purchase
Articles]
Cholesterol Metabolism and Brain Amyloidosis: Evidence
for a Role of Copper in the Clearance of Aβ
Through the Liver Pp. 165-169
D. Larry Sparks
[Abstract] [Purchase
Articles]
Role of LXR and ABCA1 in the Pathogenesis of Alzheimer’s
Disease – Implications for a New Therapeutic Approach
Pp. 171-178
Radosveta Koldamova and Iliya Lefterov
[Abstract] [Purchase
Articles]
Liver X Receptor-Mediated Gene Regulation and Cholesterol
Homeostasis in Brain: Relevance to Alzheimer’s Disease
Therapeutics Pp. 179-184
Guoqing Cao, Kelly R. Bales, Ronald B. DeMattos and Steven
M. Paul
[Abstract] [Purchase
Articles]
Systemic Inflammation, Infection, ApoE Alleles, and
Alzheimer Disease: A Position Paper Pp. 185-189
Caleb E. Finch and Todd E. Morgan
[Abstract] [Purchase
Articles]
Role of the Blood-Brain Barrier in the Pathogenesis
of Alzheimer’s Disease Pp. 191-197
Rashid Deane and Berislav V. Zlokovic
[Abstract] [Purchase
Articles]
Glucocorticoids, the Etiology of Obesity and the Metabolic
Syndrome Pp. 199-204
Mary F. Dallman, Susan F. Akana, Norman C. Pecoraro, James
P. Warne, Susanne E. la Fleur and Michelle T. Foster
[Abstract] [Purchase
Articles]
A New Glucocorticoid Hypothesis of Brain Aging: Implications
for Alzheimer’s Disease, 2007, 4, 205-212
Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen and
Nada M. Porter
[Abstract] [Purchase
Articles]
Gestational Programming of Offspring Obesity: A Potential
Contributor to Alzheimer’s Disease Pp. 213-217
Michael G. Ross, Mina Desai, Omid Khorram, Robert A. McKnight,
Robert H. Lane and John Torday
[Abstract] [Purchase
Articles]
How and When Environmental Agents and Dietary Factors
Affect the Course of Alzheimer’s Disease: The “LEARn”
Model (Latent Early-Life Associated Regulation) May Explain
the Triggering of AD Pp. 219-228
Debomoy K. Lahiri, Bryan Maloney, Md Riyaz Basha, Yuan
Wen Ge and Nasser H. Zawia
[Abstract] [Purchase
Articles]
Leon
Thal and the Alzheimer’s Disease Cooperative Study
Pp. 229-230
Lon S. Schneider
Abstracts
[Back to top]
Editorial: Exploring the Links between Obesity and Alzheimer’s
Disease
Suzana S. Petanceska
There is a worldwide increase in obesity and this increase
is of epidemic proportions in the United States [1]. In the
last few years, a number of epidemiological studies have pointed
to a link between obesity at midlife and the risk of late-life
dementia and Alzheimer’s disease (AD) [2]. Obesity is
a key component of metabolic syndrome which is defined as
a clustering of central adiposity, insulin resistance, atherogenic
dyslipidemia, hypertension, and endothelial dysfunction. Epidemiological
data have also found an association between metabolic syndrome
and accelerated cognitive decline in non-demented elderly
individuals. This negative impact is further accentuated in
individuals with high levels of inflammatory markers in their
circulation [3]. Individual components of metabolic syndrome,
such as insulin resistance, midlife hypercholesterolemia and
hypertension also correlate with increased risk of developing
AD [4]. In light of these findings and given the rise in childhood
obesity [5] and the prevalence of obesity and metabolic syndrome
in the US, there is a need to stimulate research that would
examine the possible link between obesity, as well as other
components of metabolic syndrome, and AD and to delineate
the molecular mechanisms by which disrupted systemic metabolism
may influence the transition between normal brain aging and
Alzheimer’s disease. As a first step towards this goal
the National Institute on Aging (NIA) convened a
two-day multidisciplinary workshop that brought together basic
research scientists, epidemiologists and clinicians from academia
as well as from the pharmaceutical industry. The scientific
background of the speakers spanned neuroscience, physiology,
endocrinology and genetics. In addition to the 21 speakers,
the workshop convened about 40 guests from the NIA, the National
institute of Neurological Disorders and Stroke, National Institute
of Diabetes and Digestive and Kidney Diseases, the Office
of Dietary Supplements, and other relevant organizations such
as the Alzheimer’s Association, the Institute for the
Study of Aging, the American Diabetes Association, and the
Food and Drug Administration. The workshop was co-sponsored
by the Office of Dietary Supplements at the National Institute
of Health and by the Alzheimer’s Association.
The participants of this exploratory workshop critically appraised
the current state of knowledge on the subject of obesity,
metabolic syndrome and cognition as it relates to AD. This
Special Issue brings an array of minireviews, position papers
and original research articles contributed by the workshop
participants and their colleagues. The authors present a number
of new ideas as to how this complex subject can be addressed
for the purpose of advancing our understanding and treatment
of AD. Some of the questions raised at the workshop and in
this issue are:
• Do obesity and other components of the metabolic syndrome
influence normal brain aging and the transition between normal
brain aging and AD, and if so, by what mechanisms?
• Do individual components of the metabolic syndrome
interact to accelerate brain aging and if they do, what mechanisms
are involved?
• What is the impact of obesity, hypertension, dyslipidemia
and systemic proinflammatory state on the cerebrovasculature
and the neurovascular unit?
• Are there late-life cognitive consequences of over-feeding
or underfeeding early in life and during development?
• Does early programming play a role in the etiology
of sporadic Alzheimer’s disease and, if it does, which
epigenetic mechanisms are involved?
• Do the hypothalamic-pituitary axis and glucocorti-coids
have a role in translating the disruption in systemic metabolic
homeostasis to AD-related neurodegeneration and, if so, by
what mechanisms?
• If certain components of the metabolic syndrome are
in the causal pathway to AD or contribute to its progression
what are the new therapeutic targets and modalities that we
can address?
Most of these questions have yet to be answered and highlight
some of the avenues of future research which promise to advance
our understanding of the etiology of AD and to expand the
therapeutic possibilities for prevention and treatment of
this devastating disease. What is apparent however is that
to gain a better understanding of AD we need to begin thinking
“outside of the brain” and that some of the events
that trigger changes leading to the late-life expression of
this disease may occur early in childhood and even in
utero.
REFERENCES
[1] Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabal CJ,
Flegal KM. Prevalence of overweight and obesity in the United
States, 1999-2004. JAMA 295:1549-1555 (2006).
[2] Gorospe EC, Dave JK. The risk of dementia with increased
body-mass index: a systematic review. Age Ageing (2006) Epub
ahead of print.
[3] Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T,
Shorr RI, Tylavsky FA, Newman AB. The metabolic syndrome,
inflammation, and risk of cognitive decline. JAMA 292:2237-2242
(2004).
[4] Rosano C, Newman. Cardiovascular disease and risk of Alzheimer’s
Disease. Neurol. Res. 28:612-620 (2006).
[5] Li C, Ford ES, Mokdad AH, Cook S. Recent trends in waist
circumference and waist-height ratio among US children and
adolescents. Pediatrics 111:e1390-1398 (2006).
[Back to top]
[Purchase
Articles]
An Introduction to Obesity and Dementia
Elizabeth Barrett-Connor
The increasing prevalence of obesity world-wide has an expected
consequent increase in diabetes and cardiovascular disease.
Less attention has been paid to the effect of obesity on dementia.
This overview discusses methodological issues related to the
epidemiologic study of obesity and dementia, reviews results
of long-term prospective studies, and briefly considers possible
mechanisms for an obesity-dementia association. At least six
cohort studies of 18 to 32 years duration confirm that overweight
middle-aged or older adults are at increased risk of dementia
in later life. In many of these studies, the association persisted
after adjusting for classical cardiovascular risk factors.
A few epidemiologic studies (and more laboratory studies not
reviewed here) suggest biomarkers such as C-reactive protein,
interleukin 6, and leptin may explain part of the obesity-dementia
connection. If any of these factors are in the causal pathway
to dementia, their reversal or prevention by weight control
would have huge public health importance.
[Back to top]
[Purchase
Articles]
Body Mass Index in Midlife and Risk of Alzheimer Disease
and Vascular Dementia
Rachel A. Whitmer, Erica P. Gunderson, Charles P. Quesenberry
Jr, Jufen Zhou and Kristine Yaffe
Prior work has suggested that obesity and overweight as measured
by body mass index (BMI) increases risk of dementia. It is
unknown if there is a difference in the risk of developing
Alzheimer disease (AD) versus vascular dementia (VaD) associated
with high body weight. The goal of this study was to examine
the association between midlife BMI and risk of both AD and
VaD an average of 36 years later in a large (N= 10,136) and
diverse cohort of members of a health care delivery system.
Participants aged 40-45 participated in health exams between
1964 and 1968. AD and VaD diagnoses were obtained from Neurology
visits between January 1, 1994 and June 15, 2006. Those with
diagnoses of general dementia from primary care providers
were excluded from the study. BMI was analyzed in WHO categories
of under-weight, overweight and obese, as well as in subdivisions
of WHO categories. All models were fully adjusted for age,
education, race, sex, marital status, smoking, hyperlipidemia,
hypertension, diabetes, ischemic heart disease and stroke.
Cox proportional hazard models showed that compared to those
with a normal BMI (18.5-24.9), those obese (BMI ≥ 30)
at midlife had a 3.10 fold increase in risk of AD (fully adjusted
model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold
increase in risk of VaD (fully adjusted model, HR=5.01, 95%
CI 2.98-8.43) while those overweight ( BMI ≥ 25 and
<30) had a two fold increase in risk of AD and VaD (fully
adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95,
95% CI 1.29-2.96 for VaD). These data suggest that midlife
BMI is strongly predictive of both AD and VaD, independent
of stroke, cardiovascular and diabetes co morbidities. Future
studies need to unveil the mechanisms between adiposity and
excess risk of AD and VaD.
[Back to top]
[Purchase
Articles]
Relation of Obesity to Cognitive Function: Importance
of Central Obesity and Synergistic Influence of Concomitant
Hypertension. The Framingham Heart Study
Philip A. Wolf, Alexa Beiser, Merrill F. Elias, Rhoda
Au, Ramachandran S. Vasan and Sudha Seshadri
Background: Obesity has been related to the
incidence of dementia but its impact on cognitive performance
in persons without dementia is less clear. We hypothesized
that mid-life obesity may modulate the impact of conventional
cardiovascular risk factors (CVRF) on cognitive impairment.
We tested this hypothesis in the community-based Framingham
Offspring Study sample.
Methods: At Examination cycle 4 (1988-90)
of the Offspring Cohort, indices of obesity (BMI and Waist-Hip
Ratio [WHR]) and baseline CVRF levels were ascertained in
1,814 men and women, aged 40-69 years. Obesity and hypertension
were related to the score on each of 8 neurocognitive tests
measured at Examination 8, 12 years later (1999-2002).
Results: Midlife measures of central obesity
(WHR in the uppermost quartile- Q4) and of hypertension (BP
≥140/≥90 or use of anti-hypertensive medication)
were each significantly related to poorer performance on executive
function & visuomotor skills (Trails B, Visual Reproductions-Immediate
and Delayed Recall). Further, the relation of hypertension
to neurocognitive performance was significantly modified by
WHR; hypertension was not associated with neurocognitive performance
in WHR Q1-Q3, but was associated with a marked adverse performance
in Q4 WHR. Neither HTN nor obesity was individually or synergistically
related to verbal memory (immediate or delayed recall).
Conclusions: Executive function and visuomotor
skills were differentially affected by the combined presence
of midlife hypertension and Q4 WHR while measures of verbal
memory function were not related to these risk factors in
our sample, a pattern consistent with vascular cognitive impairment.
Control of mid-life elevated blood pressure and central obesity
may be strategies to reduce cognitive decline with age.
[Back to top]
[Purchase
Articles]
The Epidemiology of Adiposity and Dementia
Rachel A. Whitmer
Adipose tissue is the largest endocrine gland in the body,
yet only recently has its role in neurodegenerative disease
been considered. Prospective population level evidence has
emerged to show that both obesity and overweight, is associated
with an increased risk of all cause dementia, Alzheimer’s
disease (AD), and underlying neurodegenerative changes. Weight
loss in late life however is associated with dementia, and
those categorized as underweight are also at a greater risk
of dementia. Given the current epidemic of obesity, and the
expected age-related increase in dementia incidence, even
a small association between these two diseases has far reaching
public health implications. However, due to the effects of
both AD-associated weight loss and age-related changes in
body composition, there are methodological challenges in appropriately
evaluating obesity as a risk factor for developing dementia.
There is a need to take a ‘life course approach’
and to consider the role of risk factors prior to the onset
of old age. Our work has shown that both obesity and overweight,
as measured by body mass index and skinfold thickness, in
middle-age are strongly associated with an increased risk
of all cause dementia, Alzheimer disease & Vascular dementia,
independent of the development of diabetes and cardiovascular-related
morbidities. There is also value in assessing regional body
shape distributions of adiposity, particular the role of abdominal
obesity. Mechanistic pathways such as adipocyte secreted proteins
and hormones, and inflammatory cytokines could explain the
association between obesity and increased risk of dementia.
[Back to top]
[Purchase
Articles]
Metabolic Syndrome and Cognitive Decline
Kristine Yaffe
Over 33% of women and 20% of men aged 65 and older will develop
dementia during their lifetime, and many more will develop
a milder form of cognitive impairment. Given the anticipated
exponential increase in both the incidence and prevalence
of cognitive impairment in the next century, it is critical
to identify preventative strategies to thwart this critical
public health issue. The metabolic syndrome is comprised of
five cardiovascular risk factors that include abdominal obesity,
hypertriglyceridemia, low high density lipoprotein (HDL) levels,
hypertension, and hyperglycemia. The prevalence of the metabolic
syndrome, similar to that for cognitive disorders, increases
dramatically with age. While several of the individual components
of the metabolic syndrome have been linked to risk of developing
dementia and cognitive impairment, few studies have looked
at the components of the metabolic syndrome as a whole. We
found, in two separate studies involving elders of different
ethnicities, that the metabolic syndrome is a risk factor
for accelerated cognitive aging. This was especially true
for elders with the metabolic syndrome and with elevated serum
level of inflammation. Several possible mechanisms may explain
the association between the metabolic syndrome and cognitive
decline including micro- and macro-vascular disease, inflammation,
adiposity and insulin resistance. If metabolic syndrome is
associated with increased risk of developing cognitive impairment,
regardless of mechanism, then early identification and treatment
of these individuals might offer avenues for disease course
modification.
[Back to top]
[Purchase
Articles]
Adiposity and Alzheimer’s Disease
Jose A. Luchsinger and Richard Mayeux
The objective of this manuscript is to provide a comprehensive
review of the relation between adiposity and Alzheimer’s
disease (AD), its potential mechanisms, and issues in its
study.
Adiposity represents the body fat tissue content. When the
degree of adiposity increases it can be defined as being over-weight
or obese by measures such as the body mass index. Being overweight
or obese is a cause of hyperinsulinemia and diabetes, both
of which are risk factors for AD. However, the epidemiologic
evidence linking the degree of adiposity and AD is conflicting.
Traditional adiposity measures such as body mass index have
decreased validity in the elderly. Increased adiposity in
early or middle adult life leads to hyperinsulinemia which
may lead to diabetes later in life. Thus, the timing of ascertainment
of adiposity and its related factors is critical in understanding
how it might fit into the pathogenesis of AD. We believe that
the most plausible mechanism relating adiposity to AD is hyperinsulinemia,
but it is unclear whether specific products of adipose tissue
also have a role. Being overweight or obese is increasing
in children and adults, thus understanding the association
between adiposity and AD has important public health implications.
[Back to top]
[Purchase
Articles]
What Can Imaging Reveal about Obesity and the Brain?
William Jagust
Brain imaging has played a major role in exploring abnormalities
of brain structure and function in aging and dementia. Recently,
with reports linking obesity to cognitive decline and dementia,
magnetic resonance imaging has been used to investigate how
brain structure may be altered with obesity. These studies
have convincingly demonstrated both generalized and regional
brain atrophy and changes in white matter in association with
obesity. These results do not appear to be simply explained
by links to cardiovascular disease. However, the mechanisms
underlying these alterations are unclear and could be accounted
for by a number of different processes that are known to alter
brain structure and which could also be related to obesity.
Application of additional imaging methods could help to establish
the pathway through which obesity produces cognitive decline
and dementia.
[Back to top]
[Purchase
Articles]
Next Steps in Alzheimer’s Disease Research:
Interaction between Epidemiology and Basic Science
Lenore J. Launer
Epidemiologic studies have provided important clues about
the etiology, prognosis and options for prevention and treatment
of AD, and sub-clinical changes in cognition and brain structure.
A brief review is given of what we have learned from epidemiologic
studies of risk factors and natural history. This is followed
by a discussion of how these findings could inform the design
of basic research strategies that may further the translation
of bench science to the clinic and public health arena.
[Back to top]
[Purchase
Articles]
Animal Models of Obesity and Metabolic Syndrome: Potential
Tools for Alzheimer’s Disease Research
Kristin M. Abraham
Emerging evidence suggests that components of the metabolic
syndrome either in isolation or in aggregate may impact the
onset or severity of neurodegenerative processes, including
those physiologic changes that lead to Alzheimer’s Disease
(AD). Several animal models that were originally designed
to interrogate the metabolic syndrome are readily available.
These models can now be used to support studies that may provide
new mechanistic links between the metabolic syndrome and neurodegeneration.
In addition, animal strains currently being generated and
phenotyped through the efforts of an array of NIDDK-supported
projects are likely to provide novel and better tools to advance
Alzheimer’s disease research in the near future.
[Back to top]
[Purchase
Articles]
Insulin Resistance and Alzheimer’s Disease Pathogenesis:
Potential Mechanisms and Implications for Treatment
Suzanne Craft
Insulin modulates cognition and other aspects of normal brain
function. Insulin resistance is characterized by chronic peripheral
insulin elevations, and it is accompanied by reduced brain
insulin levels and insulin activity. Obesity, type 2 diabetes
mellitus and hypertension are strongly associated with insulin
resistance. In addition, insulin resistance increases the
risk of age-related memory impairment and Alzheimer’s
disease. Possible mechanisms through which these risks are
increased include the effects of peripheral hyperinsulinemia
on memory, CNS inflammation, and regulation of the β-amyloid
peptide. We have shown that raising plasma insulin in humans
to levels that characterize patients with insulin resistance
increases the levels of Aβ
and inflammatory agents in brain. These convergent effects
may impair memory and induce AD pathology. Therapeutic strategies
focused on preventing or correcting insulin abnormalities
may thus benefit a subset of adults with age-related memory
impairment and AD.
[Back to top]
[Purchase
Articles]
Insulin Resistance, Glycemic Control and Adiposity:
Key Determinants of Healthy Lifespan
Peter S. DiStefano, Rory Curtis and Bradley J. Geddes
Identification of genes and pathways that alter lifespan has
allowed for new insights into factors that control the aging
process as well as disease. While strong molecular links exist
between aging and metabolism, we hypothesize that targeting
the mechanisms involved in aging will also give rise to therapeutics
that treat other devastating age-related diseases, such as
neurodegeneration, cancer, inflammation and cardiovascular
disease. Insulin sensitivity, glycemic control and adiposity
are not only hallmarks of the major metabolic diseases, type
2 diabetes and obesity, but they also represent significant
risk factors for the development of Alzheimer’s Disease
and cognitive impairment. Insulin/IGF-1 signaling is an important
pathway regulating aging and disease in a variety of species,
including mammals. Here we describe an important role for
the gut-derived peptide ghrelin in upstream signaling through
the insulin/IGF-1 pathway and exemplify modulation of ghrelin
signaling as an approach to mechanistic treatment of multiple
age-related diseases by virtue of its ability to regulate
key metabolic functions.
[Back to top]
[Purchase
Articles]
Therapeutic Use of Agonists of the Nuclear Receptor
PPARγ
in Alzheimer’s Disease
Gary Landreth
Alzheimer’s disease (AD) is a devastating neurodegenerative
disease for which there are no highly effective therapies.
A novel therapeutic approach to the treatment of AD is the
use of agonists of the nuclear receptor, peroxisome proliferators-activated
receptor gamma (PPARγ).
PPARγ
is a ligand activated transcription factor whose best described
roles are to regulate lipid metabolism and inflammation. Agonists
of PPARγ
have been shown to ameliorate AD-related pathology in animal
models of AD and improve cognition. A number of potential
mechanisms have been advanced to account for these effects.
PPARγ
agonists act as insulin sensitizers, facilitating insulin
action. In addition, PPARγ
agonists have been shown to inhibit inflammatory gene expression,
alter Aβ
homeostasis and exhibit neuroprotective effects. Importantly,
recent clinical trials of FDA approved PPARγ
agonists have been shown to improve cognition and memory in
AD patients. Thus, PPARγ
agonists represent a new and potentially efficacious treatment
of AD.
[Back to top]
[Purchase
Articles]
Cholesterol Metabolism and Brain Amyloidosis: Evidence
for a Role of Copper in the Clearance of Aβ
Through the Liver
D. Larry Sparks
Mounting evidence suggests that copper may influence the progression
of Alzheimer’s disease by reducing clearance of the
amyloid beta protein (Aβ)
from the brain. We propose that Aβ
is cleared from the brain by tagging along with cholesterol/ApoE
in traversing the BBB, with subsequent incorporation into
HDL for delivery of the toxin to the liver. It is suggested
that either ABC-A1 or LRP, or both are involved in Aβ
transport across the BBB, as well as normal cholesterol efflux.
We have previously shown that addition of only 0.12 PPM copper
(one-tenth the Environmental Protection Agency Human consumption
limits) to distilled water was sufficient to precipitate the
accumulation of Aβ
in the brains of cholesterolfed rabbits. Here we show that
in a setting of elevated cholesterol levels, overproduced
Aβ
is cleared to the blood and can simultaneously be identified
in the liver if copper ion is absent from the animal’s
drinking water, but if trace levels copper (0.12 PPM) are
added to the drinking water Aβ
accumulates in the brain, while the levels in the liver are
greatly reduced.
[Back to top]
[Purchase
Articles]
Role of LXR and ABCA1 in the Pathogenesis of Alzheimer’s
Disease – Implications for a New Therapeutic Approach
Radosveta Koldamova and Iliya Lefterov
Studies, ranging from epidemiological to in vitro
and in vivo experimental settings have provided convincing
evidence that different aspects of brain lipid metabolism
may influence Alzheimer disease pathogenesis through effects
on β-amyloid
deposition and clearance. It has been demonstrated that transcription
factors called nuclear liver X receptors (LXR) and their responsive
genes provide natural regulatory mechanisms and influence
AD pathogenesis through their modulatory effects on intracellular
cholesterol content, cholesterol efflux and possibly via
anti-inflammatory mechanisms. Here, we provide a brief summary
of the approaches undertaken by different groups that lead
to the nowadays working model of LXR and ABCA1 regulatory
role in brain amyloidogenesis and amyloid clearance and we
highlight the therapeutic potential of LXR agonists.
[Back to top]
[Purchase
Articles]
Liver X Receptor-Mediated Gene Regulation and Cholesterol
Homeostasis in Brain: Relevance to Alzheimer’s Disease
Therapeutics
Guoqing Cao, Kelly R. Bales, Ronald B. DeMattos and Steven
M. Paul
Liver X receptors (LXRα
and LXRβ)
are oxysterol receptors that function as master transcription
factors mediating cholesterol homeostasis in the periphery.
LXRs regulate the levels of the ABCA1 and ABCG1 cholesterol
transporters as well as apolipoproteins (apoE and apoC) in
various cells thereby affecting cholesterol transport and
metabolism. In the brain, LXRs regulate ABCA1 in both neurons
and glia resulting in cholesterol efflux from these cells.
In addition, the expression of apolipoprotein E (apoE), synthesized
primarily by astrocytes and microglia, is also upregulated
by LXR agonists. As both apoE and the ABCA1 transporter are
intimately involved in amyloid-β
peptide (Aβ)
transport and clearance, activation of these genes by LXR
agonists in brain may have a significant impact on Aβ
deposition and amyloid/neuritic plaque formation. Furthermore,
LXR activation has been shown to have significant anti-inflammatory
properties. Taken together, these findings suggest that brain-penetrable
LXR agonists or modulators may be useful therapeutic agents
for the treatment and (or) prevention of Alzheimer’s
disease.
[Back to top]
[Purchase
Articles]
Systemic Inflammation, Infection, ApoE Alleles, and
Alzheimer Disease: A Position Paper
Caleb E. Finch and Todd E. Morgan
Alzheimer disease (AD) includes inflammatory processes in
the senile plaques and surrounding glia, with increased expression
of acute phase proteins such as C-reactive protein (CRP) and
IL-6. Increased IL-6 expression during normal brain aging
suggests a link of age-related inflammation to the onset of
AD during aging. Blood levels of CRP and IL-6 are also associated
with higher risk of Alzheimer disease and cognitive decline
during aging. Some infections are known to induce inflammation
and amyloid deposits. For example, HIV induces the deposition
of the same beta-amyloid as in Alzheimer disease. The ApoE4
allele may increase HIV-associated dementia, in addition to
its well-known effect on accelerating the onset age of AD.
Many other adverse effects of apoE4 are recognized, which
suggested the hypothesis that apoE4 persists in human populations
because of balancing selection (Charlesworth-Martin hypothesis).
The apoE4 allele was acquired during human evolution and may
have conferred initial advantages in pathogen resistance.
As evidence for this hypothesis, apoE4 carriers have less
severe liver damage during hepatitis C infections. As human
lifespan lengthened and cognitive and cardiovascular health
became more important, the apoE3 allele spread, while the
E4 allele was maintained in all populations by balancing selection.
[Back to top]
[Purchase
Articles]
Role of the Blood-Brain Barrier in the Pathogenesis
of Alzheimer’s Disease
Rashid Deane and Berislav V. Zlokovic
Cerebrovascular dysfunction contributes to the cognitive decline
and dementia in Alzheimer’s disease (AD), and may precede
cerebral amyloid angiopathy and brain accumulation of the
Alzheimer’s neurotoxin, amyloid β-peptide
(Aβ).
The blood-brain barrier (BBB) is critical for brain Aβ
homeostasis and regulates Aβ
transport via two main receptors, the low density lipoprotein
receptor related protein 1 (LRP1) and the receptor for advanced
glycation end products (RAGE). According to the neurovascular
hypothesis of AD, faulty BBB clearance of Aβ
through deregulated LRP1/RAGE-mediated transport, aberrant
angiogenesis and arterial dysfunction may initiate neurovascular
uncoupling, Aβ
accumulation, cerebrovascular regression, brain hypoperfusion
and neurovascular inflammation. Ultimately these events lead
to BBB compromise and chemical imbalance in the neuronal ‘milieu’,
and result in synaptic and neuronal dysfunction. Based on
the neurovascular hypothesis, we suggest an array of new potential
therapeutic approaches that could be developed for AD to reduce
neuroinflammation, enhance Aβ
clearance and neurovascular repair, and improve cerebral blood
flow. RAGE-based and LRP1-based therapeutic strategies have
potential to control brain Aβ
in AD, and possibly related familial cerebrovascular β-amyloidoses.
In addition, we have identified two vascularly restricted
genes, GAX (growth arrest-specific homeobox), which
controls LRP1 expression in brain capillaries and brain angiogenesis,
and MYOCD (myocardin), which controls contractility
of cerebral arterial smooth muscle cells and influences cerebral
blood flow. These findings provide insights into new pathogenic
pathways for the vascular dysfunction in AD and point to new
therapeutic targets for AD.
[Back to top]
[Purchase
Articles]
Glucocorticoids, the Etiology of Obesity and the Metabolic
Syndrome
Mary F. Dallman, Susan F. Akana, Norman C. Pecoraro, James
P. Warne, Susanne E. la Fleur and Michelle T. Foster
In mammals, glucocorticoid actions appear to have evolved
to maintain and enhance energy stores to be used for life-saving
gluconeogenesis. They act on the brain to stimulate search
behaviors, palatable feeding and emotionally relevant memories,
and they act on the body to mobilize stored peripheral energy
and direct it to central depots that serve the substrate needs
of the liver. Our work in rats shows that searching and intake
of palatable foods (sucrose, saccharin and lard) are stimulated
by corticosterone in a dose-related fashion. Adrenalectomized
rats gain weight poorly, have low fat content, increased sympathetic
neural and hypothalamo-pituitary-adrenal outflow, and altered
behaviors. Replacement with corticosterone reverses these
effects. Surprisingly, when such rats are provided with 30%
sucrose to drink, in addition to saline, all of the usual
effects of adrenalectomy are corrected without corticosterone.
We hypothesize that there is a metabolic feedback system that
decreases stress-responsiveness. Although we have not yet
identified the signal associated with sucrose drinking, the
weight of mesenteric fat correlates inversely with hypothalamic
corticotropin-releasing factor (CRF). When rats eat lard and
sucrose ad libitum, fat stores increase and CRF,
ACTH and corticosterone responses are reduced. During stress,
chow intake decreases but intake of lard and sucrose does
not. Our current working model suggests that palatability
signals and neural signals from fat stores act on brain to
reduce activity in the central stress response system. Correlative
results from a clinical study support the powerful role of
small changes in glucocorticoids in type 2 diabetes.
[Back to top]
[Purchase
Articles]
A New Glucocorticoid Hypothesis of Brain Aging: Implications
for Alzheimer’s Disease
Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen and
Nada M. Porter
The original glucocorticoid (GC) hypothesis of brain aging
and Alzheimer’s disease proposed that chronic exposure
to GCs promotes hippocampal aging and AD. This proposition
arose from a study correlating increasing plasma corticosterone
with hippocampal astrocyte reactivity in aging rats. Numerous
subsequent studies have found evidence consistent with this
hypothesis, in animal models and in humans. However, several
results emerged that were inconsistent with the hypothesis,
highlighting the need for a more definitive test with a broader
panel of biomarkers. We used microarray analyses to identify
a panel of hippocampal gene expression changes that were aging-dependent,
and also corticoster-one-dependent. These data enabled us
to test a key prediction of the GC hypothesis, namely, that
the expression of most target biomarkers of brain aging should
be regulated in the same direction (increased or decreased)
by both GCs and aging. This prediction was decisively contradicted,
as a majority of biomarker genes were regulated in opposite
directions by aging and GCs, particularly inflammatory and
astrocyte-specific genes. Thus, the initial hypothesis of
simple positive co-operativity between GCs and aging must
be rejected. Instead, our microarray data suggest that in
the brain GCs and aging interact in more complex ways that
depend on the cell type. Therefore, we propose a new version
of the GC-brain aging hypothesis; its main premise is that
aging selectively increases GC efficacy in some cell types
(e.g., neurons), enhancing catabolic processes, whereas aging
selectively decreases GC efficacy in other cell types (e.g.,
astrocytes), weakening GC anti-inflammatory activity. We also
propose that changes in GC efficacy might be mediated in part
by cell type specific shifts in the antagonistic balance between
GC and insulin actions, which may be of relevance for Alzheimer’s
disease pathogenesis.
[Back to top]
[Purchase
Articles]
Gestational Programming of Offspring Obesity: A Potential
Contributor to Alzheimer’s Disease
Michael G. Ross, Mina Desai, Omid Khorram, Robert A. McKnight,
Robert H. Lane and John Torday
Obesity and its related diseases are the leading cause of
death in western society, with associated risks of hypertension,
coronary heart disease, stroke, diabetes, and breast, prostate
and colon cancer. Recent epidemiologic data indicate an increased
risk of Alzheimer’s disease in association with adult
obesity. There is now convincing evidence that, in both human
and animal models, the in utero environment may impact
on fetal developmental processes, altering offspring homeostatic
regulatory mechanisms. “Gestational programming”
may result in altered cell number, organ structure, hormonal
set points or gene expression, with effects being permanent
or expressed only at select offspring ages (e.g., newborn,
adult). Our laboratory and others have demonstrated that low
birth weight rats, induced by maternal food restriction or
uterine artery ligation, paradoxically develop adult obesity
with glucose intolerance and hypertension. Recent studies
indicate alterations in peripheral (hepatic) and central (hippocampus)
IGF-1 gene expression and epigenetic regulation among these
offspring. These findings suggest that potential risk factors
for the development of Alzheimer’s disease may be present
as early as newborn life.
[Back to top]
[Purchase
Articles]
How and When Environmental Agents and Dietary Factors
Affect the Course of Alzheimer’s Disease: The “LEARn”
Model (Latent Early-Life Associated Regulation) May Explain
the Triggering of AD
Debomoy K. Lahiri, Bryan Maloney, Md Riyaz Basha, Yuan
Wen Ge and Nasser H. Zawia
Alzheimer’s disease (AD) is currently the most prominent
form of dementia among the elderly. Although AD manifests
in late adult life, it is not clear when the disease actually
starts and how long the neuropathological processes take to
develop AD. The major unresolved question is the timing and
the nature of triggering leading to AD. Is it an early or
developmental and/or late phenomenon and what are the factors
that trigger the cascade of pathobiochemical processes? To
explain the etiology of AD one should consider the neuropathological
features, such as neuronal cell death, t tangles,
and amyloid plaque, and environmental factors associated with
AD, such as diet, toxicological exposure, and hormonal factors.
Current dominant theories of AD etiology are “protein–only”,
they attribute the cause of the disease directly to the activities
of associated proteins once they have been produced; the major
limitation is that protein aggregations occur “late
in the game”. Development and progression of AD has
not been explained by protein–only models. In view of
this limitation, we propose a “Latent Early-Life Associated
Regulation” (LEARn) model, which postulates a latent
expression of specific genes triggered at the developmental
stage. According to this model, environmental agents (e.g.,
heavy metals), intrinsic factors (e.g., cytokines), and dietary
factors (e.g., cholesterol) perturb gene regulation in a long–term
fashion, beginning at early developmental stages; however,
these perturbations do not have pathological results until
significantly later in life. For example, such actions would
perturb APP gene regulation at very early stage via its transcriptional
machinery, leading to delayed overexpression of APP and subsequently
of Aβ
deposition. This model operates on the regulatory region (promoter)
of the gene and by the effect of methylation at certain sites
within the promoter of specific genes. Promoters tend to have
both positive and negative regulatory elements, and promoter
activity can be altered by changes in the primary DNA sequence
and by epigenetic changes through mechanisms such as DNA methylation
at CpG dinucleotides or oxidation of guanosine residues. The
basis of the LEARn model is that environmental factors, including
metals and dietary factors, operate by interfering the interaction
of methylated CpG clusters with binding proteins, such as
MeCP2 and SP1. The LEARn model may explain the etiology of
AD and other neuropsychiatric and developmental disorders.
|
