Volume 1, Numbers
4-5, Guest Editor: James Geddes, November 1999
Pages 197-201
William B. Grant
Dietary Links to Alzheimer's Disease
Summary: With the republication of Grant [1997], the first
paper providing epidemiologic evidence linking diet to the
development of Alzheimer’s disease (AD), it is an appropriate time
to review the findings and hypotheses therein in light of the
subsequent literature. The main findings, that dietary fat and
energy in old age are high risk factors, while fish and cereals are
risk-reduction factors, have been supported in various recent
epidemiologic studies. Diet contributes to the development of AD
through modulating oxidative stress and inflammation, which is also
linked to oxidative stress, but may also arise from series 2
prostaglandins. Thus, as one ages, dietary modifications and
additional supplements designed to reduce free radical production
and inflammation provide a significant measure of reduction in risk
for the development of AD.
Pages 203-206
Mark A. Smith, Grace J. Petot, and George Perry
Commentary: Diet and Oxidative Stress: A Novel Synthesis of
Epidemiological Data on Alzheimer's Disease
Summary: In an innovative synthesis, William B. Grant links
Alzheimer’s disease to diet by combining the prevalence of
Alzheimer’s disease in several countries with a meta-analysis of
community-based studies of diet [Grant, 1997]. A positive
relationship between caloric, as well as fat, intake and the
prevalence of Alzheimer’s disease is demonstrated. These findings
link Alzheimer’s disease to diet in a more general sense than
previous studies that focused instead on specific dietary components
such as consumption of brain, raw meat, seafood, alcohol, coffee or
vitamin supplements. These latter studies usually had the single
goal of determining whether food-borne pathogens or toxins might be
implicated, rather than focusing on foods as a source of nutrients.
Pages 207-219
Andrea Wevers and Hannsjörg Schröder
Nicotinic Acetylcholine Receptors in Alzheimer's Disease
Summary: Nicotinic cholinoceptive dysfunction associated with
cognitive impairment is a leading neurochemical feature of
Alzheimer’s disease. Therefore, nicotinic acetylcholine receptors
have attracted considerable interest as potential therapeutic
targets. The deficit of nicotine binding sites in Alzheimer's
disease may be related to alterations of nicotinic receptor
synthesis on the levels of (i) transcription, (ii) translation and
post-translational modifications, (iii) receptor transport and
turnover, including membrane insertion. Current approaches aim at
the elucidation of molecular changes at all three levels. Although a
comprehensive picture has not yet been achieved, currently available
data can be summarized as follows: (i) there are no changes at the
level of transcription of subunit mRNAs studied so far, (ii)
evidence is accumulating for a distinct decrease on the protein
level in the expression especially of the alpha4-subunit, and (iii)
preliminary findings point to a possible correlation of cytoskeletal
changes (hyperphosphorylation of tau-protein) with decreased
nicotinic acetylcholine receptor expression.
Pages 221-230
James R. Pauly, Ph.D.
Nicotinic cholinergic receptor deficits in Alzheimer's Disease:
Where's the smoke?
Summary: Receptor binding studies have uniformly found a
significant reduction in the density of neuronal nicotinic
cholinergic receptors in postmortem tissue obtained from Alzheimer's
Disease (AD) patients. Nicotine is widely recognized as an
pharmacological agent that facilitates cognitive performance in
human smokers as well as preclinical models utilizing rodents or
non-human primates. Furthermore, epidemiological studies have
consistently shown that the incidence of neurodegenerative diseases
such as AD and Parkinson's Disease is lower in cigarette smokers
than age-matched controls. These findings have prompted speculation
that brain nicotinic receptors could be important therapeutic
targets for Alzheimer's Disease. However, many questions remain with
regard to the specificity and significance of the findings that have
been reported with brain nicotinic receptors and AD. Few studies
have controlled for the potential influence of cigarette smoking,
which increases the density of nicotinic receptors in human smokers.
Questions also remain concerning alterations in individual nicotinic
receptors subtypes as well as the regional variability of the
deficits previously reported in AD. Therefore, although the findings
related to nicotinic receptors and AD to this date are intriguing,
they appear to have raised more questions than they have answered.
Pages 231-247
Dennis T. Villareal and John C. Morris
The Diagnosis of Alzheimer’s Disease
Summary: Dementia constitutes a growing public health crisis.
Early and accurate diagnosis of dementia is essential in order to
provide patient and family counseling and appropriate treatment,
including with specific antidementia drugs as they become
increasingly available. Age-related cognitive decline, as compared
with dementia, does not seriously interfere with usual activities.
The optimal approach to early detection of dementia is clinical
examination that incorporates information from a reliable collateral
source about how the patient’s cognitive abilities have declined
relative to past performance. Alzheimer’s disease (AD), the most
common cause of dementia, can be diagnosed clinically with high
accuracy (>85%) using standardized criteria. Even incipient AD can
be detected with clinical methods alone. Although the typical
picture of AD is characterized by gradual onset and progression of
memory and other cognitive deficits, in other respects the disease
is marked by heterogeneity. Early and late-onset AD represent the
most easily recognized subtypes. Research continues towards
characterizing a biologic marker but, as of yet, no candidate marker
surpasses the high diagnostic accuracy of clinical assessments
alone. At present, the diagnosis of AD rests primarily in the hands
of the clinician.
Pages 249-263
Dena B. Dubal, Melinda E. Wilson and Phyllis M. Wise
Estradiol: A Protective and Trophic Factor in the Brain
Summary: In recent years our appreciation that estradiol is
truly a pleiotropic hormone has grown dramatically. We will review
the findings that suggest that estrogens may exert important
non-reproductive actions on the brain. These studies provide
important insights into the clinical effects of estrogen replacement
therapy on age- and disease-related processes in the brain. We will
also discuss the multiple cellular and molecular mechanisms that may
underlie estradiol’s neurotrophic and neuroprotective effects.
Pages 265-274
David H. Small, Heidi L. Clarris, Timothy G. Williamson, Gullveig
Reed, Brian Key, Su San Mok, Konrad Beyreuther, Colin L. Masters,
Victor Nurcombe
Neurite-outgrowth regulating functions of the amyloid protein
precursor of Alzheimer's disease
Summary: Many studies have shown that breakdown of the
amyloid protein precursor (APP) to produce the amyloid protein is an
important step in the pathogenic mechanism which causes Alzheimer's
disease (AD). However, little is known about the normal function of
APP. Developmental studies show that APP expression increases during
the period of brain development when neurite outgrowth and
synaptogenesis are maximal. APP is expressed highly within growing
neurites and in growth cones, and purified APP has been shown to
stimulate neurite outgrowth from cells in culture. Thus APP may
regulate neurite outgrowth or synaptogenesis in vivo. APP is
actively secreted from many cells, and the C-terminally secreted APP
has been shown to associate with components of the extracellular
matrix, such as the heparan sulphate proteoglycans (HSPGs). Two
putative heparin-binding domains on APP have been reported. Binding
of HSPGs to an N-terminal heparin-binding domain (HBD-1) stimulates
the effect of substrate-bound APP on neurite outgrowth. In the
mature nervous system, APP may play an important role in the
regulation of wound repair. It is highly likely that studies on the
normal functions of APP will shed further light on aspects of the
pathogenesis of AD.
Pages 275-285
Tsunao Saitoh and Inhee Mook-Jung
Commentary: Is Understanding the Biological Function of APP
Important in Understanding Alzheimer's Disease?
Summary: The presence of mutations around the Abeta sequence
in APP provides strong argument for the involvement of APP, and
Abeta in particular, in pathogenesis of Alzheimer's disease (AD). In
vitro studies demonstrated that Abeta may cause neuronal death,
supporting the hypothetical involvement of Abeta in
neurodegeneration in AD. However, concentrations of Abeta required
for neuronal death are nonphysiologically high. Nevertheless, the
predominant idea in the field is that it is sufficient to postulate
Abeta as a major culprit in AD development. The question we pose is
whether the potentially important involvement of Abeta precludes the
etiological (primary) involvement (not pathological, i.e.,
secondary) of APP functions. We do not have an adequate answer to
this question. Current knowledge about APP functions indicates that
APP is critically required for the maintenance of neuronal and
synaptic structure and function. Because AD is a disease of neuronal
and synaptic deterioration, APP may be involved during the course of
AD pathogenesis, perhaps secondarily. To ponder the question whether
APP may be etiologically involved in AD, much needs to be learned
about APP functions. This article is intended to provide a
foundation for this challenging task.
Pages 287-295
Richard S. Jope
Cholinergic muscarinic receptor signaling by the phosphoinositide
signal transduction system in Alzheimer’s disease
Summary: Recent years have seen the advent of new methods
capable of measuring the activity of receptor-coupled,
G-protein-mediated, phosphoinositide second messenger production in
membranes prepared from postmortem human brain. Considering the
interest in treating Alzheimer’s disease (AD) patients with
cholinergic agonists, several investigations have used this new
methodology to analyze the functional state of cholinergic
muscarinic receptors coupled to phosphoinositide signaling directly
in AD brain. Several, but not all, reports indicate that
cholinergic agonist-induced phosphoinositide signaling is severely
impaired in AD, potentially due to impaired activation of the
receptor-coupled G-protein. Additionally, deficits in AD also have
been reported in the two second messenger pathways activated
following phosphoinositide hydrolysis, inositol-1,4,5,-triphosphate
receptor binding and protein kinase C activation, indicating further
that phosphoinositide signaling is impaired in AD. Sources of
limitations in current methodologies and issues for further
exploration are discussed. Speculation concerning potential links
between cholinergic receptor-linked signaling and early events in
the formation of amyloid plaques and neurofibrillary tangles is
provided. Especially intriguing is the potential for the
development of synergistic neurotoxicity where deficits of
phosphoinositide signaling and increased production of Aß interact
to exacerbate alterations in each process that occur in AD, leading
to a feed-forward cycle of progressive neuronal dysfunction.
Pages 297-305
John Q. Trojanowski, Christopher M. Clark, Hiroyuki Arai, and
Virginia M.-Y. Lee
Elevated Levels of Tau in Cerebrospinal Fluid: Implications for
the Antemortem Diagnosis of Alzheimer's Disease
Summary: Alzheimer's disease (AD) is a heterogeneous group of
dementias characterized by progressive cognitive impairments as well
as by the accumulation of abundant extracellular deposits of Aß and
intra-neuronal neurofibrillary lesions in selectively vulnerable
regions of the AD brain. The latter abnormalities (e.g.
neurofibrillary tangles, dystrophic neurites, neuropil threads) are
aggregates of paired helical filaments (PHFs) formed from altered
tau proteins (PHFtau). Although PHFtau and normal central nervous
system (CNS) tau are phosphorylated at nearly the same sites, PHFtau
is phosphorylated to a greater extent, and alterations in the
activity of CNS kinases and phosphatases most likely contribute to
the pathogenesis of PHFtau. Since the abundance of neurofibrillary
lesions correlates with the dementia in AD, the generation of PHFtau
and the formation of neurofibrillary lesions may be part of a cell
death pathway leading to massive neuron loss and dementia in AD.
Building upon these and other insights into altered tau metabolism
in AD, a series of recent studies suggest that the diagnosis of AD
may be supported in livingpatients by determining the concentration
of tau in cerebrospinal fluid (CSF). We review these promising
preliminary studies here, and discuss them in the context of current
understanding of the pathobiology of AD.
Pages 307-328
Gail V. W. Johnson and Scott M. Jenkins
Tau Protein in Normal and Alzheimer’s Disease Brain
Summary: In 1975, Weingarten and colleagues isolated a
protein factor that was able to induce mi-crotubule formation. They
called this factor tau. Some ten years later a new era of research
on this microtubule-associated protein was launched when several
groups almost simultaneously discovered that tau was the predominant
protein component of the paired helical filaments (PHFs) and
neurofibrillary tangles (NFTs) which are characteristic pathological
lesions of the Alzheimer’s disease brain. Subsequent findings that
PHF-tau isolated from Alzheimer’s disease brain was phosphorylated
to a greater extent than non-PHF tau, led to extensive investigation
into the posttranslational modifications (mainly phosphorylation) of
tau in normal and Alzheimer’s disease brain. The present review
highlights the literature concerning the normal functioning and
processing of tau protein, and examines the evidence for the
involvement of the abnormal posttranslational processing of tau in
the pathology of Alzheimer’s disease. Finally, speculation as to
the relationship between abnormal processing of tau, other
subcellular abnormalities seen in Alzheimer’s disease, and the
pathological causes of the disease are discussed.
Pages 329-351
Gail V. W. Johnson and Judith A. Hartigan
Tau Protein in Normal and Alzheimer’s Disease Brain: An Update
Summary: Tau is a microtubule-associated protein that, in a
hyperphosphorylated form, comprises the main component of the paired
helical filaments and neurofibrillary tangles found in Alzheimer’s
disease (AD) brain. It is therefore important to understand
the normal functioning and processing of tau protein, and the abnormal
posttranslational processing of tau in AD pathology. In 1996,
Johnson and Jenkins reviewed the literature on the biochemistry, function,
and phosphorylation of tau in normal and AD brain. Since that
time, numerous publications have come out further elucidating the
properties of tau. The present review updates the topics originally
covered in the 1996 review, as well as presents a number of new topics.
For example, mutations in the tau gene have been found in several
non-AD, autosomal dominant neurodegenerative disorders that exhibit
extensive neurofibrillary pathology. In addition, there is increasing
evidence that tau may be involved in signal transduction, organelle
transport, and cell growth, independent of its microtubule-binding
functions. Taken together, the research reviewed here demonstrates
that tau is a very complex protein with various functions that are
intricately regulated. It is clear that more research is required
to completely understand the functions and regulation of tau in normal
and AD brain.
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