| Volume 4, Number
2, April 2002
Pages 71-76
Jun Kawamata, Shun Shimohama
Association of novel and established polymorphisms in neuronal
nicotinic acetylcholine receptors with sporadic Alzheimer’s disease
Abstract: Since the loss of cholinergic neurons in the
Alzheimer’s disease (AD) brain was first reported, considerable
evidence in vivo and in vitro has accumulated in support of the
cholinergic hypothesis of AD. The hypothesis is greatly supported
by the fact that the most promising drugs against AD are inhibitors
of acetylcholinesterase (AChE). To identify the possible mutations
and/or polymorphisms of neuronal nicotinic acetylcholine receptor (nAChR)
genes related to the pathogenesis of sporadic AD, we have performed
mutational analyses of the major neuronal nAChR genes (CHRNA3, 4, 7
and CHRNB2) expressed in central nervous system. Allelic analysis
showed association of specific silent or intronic polymorphisms of
the CHRNA3 and CHRNA4 genes and AD. Two novel missense point
mutations, Ser413Leu in the CHRNA4 gene and Gln397Pro in the CHRNB2
gene, were identified in two different AD cases but were not found
in other AD cases and controls. These findings suggested that
genetic polymorphisms of the neuronal nAChR genes might be related
to the pathogenesis of sporadic AD.
Pages 77-91
Rense Lange, Carla L. Donathan, Larry F. Hughes
Assessing olfactory abilities with the University of Pennsylvania
Smell Identification Test: a Rasch scaling approach
Abstract: The strategy of delaying or retarding the
progression of Alzheimer’s disease requires early diagnosis and
treatment. Previous research indicates that measurement of changes
in olfaction and cognition will play an important role in the early
detection of AD and in the monitoring of therapy effectiveness.
Using the data of 177 subjects, our objective was to study the
measurement properties of the University of Pennsylvania Smell
Identification Test (UPSIT) using a Rasch scaling framework. The
results indicate that the UPSIT can yield a linear, unbiased, and
unidimensional Rasch measure of human smell recognition abilities.
As expected, olfactory recognition ability decreased with age, and
at the rate of about 0.05 Logits per year. Also, Alzheimer’s
patients showed a decrease in smell recognition equivalent to that
experienced by healthy subjects over the course of 30 years.
Hormone replacement therapy was not found to affect healthy women’s
olfactory recognition ability. Additional information can be
extracted from the analysis of incorrect responses patterns that is
relevant to group membership.
Pages 93-96
M. Meli, C. Perier, C. Ferron, F. Parssegny, C. Denis, R. Gonthier,
B. Laurent, E. Reynaud, J. Frey, A. Chamson (Communicated by
Craig S. Atwood)
Serum pentosidine as an indicator of Alzheimer’s disease
Abstract: Pentosidine, an advanced glycation end product
(AGE), was assayed by HPLC in serum proteins from patients with
Alzheimer type dementia (AD), patients with diabetes mellitus (D),
and healthy (C) age-matched old subjects (mean age from each group =
84 years). Serum pentosidine was significantly different between the
three groups despite similar renal function (serum creatinine < 160
µmol/L). In all groups of patients, pentosidine was independent of
glycated hemoglobin (HbA1C) and the early glycation marker
fructosamine and appeared to be an independent marker, mainly bound
to serum albumin. Pentosidine could be an important factor useful
for the diagnosis of Alzheimer's disease.
Pages 97-103
LuGuang Luo, Naohiro Yano, QuanFu Mao, IMD Jackson, EG Stopa (Communicated
by Raul Mena)
Thyrotropin releasing hormone (TRH) in the hippocampus of
Alzheimer patients
Abstract: Thyrotropin-releasing hormone (TRH) is best known
for its hypothalamic neuroendocrine role in regulating thyroid
function. In extra-hypothalamic regions in vitro, we have shown TRH
to have a protective effect against synaptic loss and neuronal
apoptosis. A role for TRH in Alzheimer’s disease (AD) has not been
established previously. In this study, we examined the content of
the TRH peptide in the hippocampus of elderly controls (n=5) and AD
patients (n=7) by radioimmunoassay (RIA). The TRH concentration was
decreased in the AD hippocampus compared to normal elderly controls
(p < 0.01). In a separate series of experiments utilizing primary
cell cultures made from rat hippocampus, TRH peptide concentration
was depleted by the addition of TRH antiserum. TRH withdrawal was
found to enhance the activity of glycogen synthetase kinase-3
(GSK-3b), a critical enzyme necessary for the phosphorylation of
tau, as well as the phosphorylation of the tau protein itself. This
TRH depletion induced upregulation in phosphorylation that was
observed to initiate axonal retraction in cultured neurons. These
data suggest that TRH within the hippocampus can regulate the
activity of various proteins by phosphorylation/dephosphorylation
that may be involved in the pathogenesis of AD.
Pages 105-114
Zafer Ali-Khan
Searching for an in vivo site for nascent amyloid fibril
formation
Abstract: Research in Alzheimer’s disease (AD), more than in
any other amyloid-related diseases, has brought together the
concerted efforts of scientists from diverse disciplines. As such,
it has advanced our understanding of the in vitro molecular
and biochemical parameters required for amyloid fibril formation.
Evidence shows that synthetic or recombinant amyloidogenic proteins
yield amyloid fibrils in vitro both in physiological and
acidic conditions. Importantly, addition of amyloid “nucleus” to
solutions containing amyloidogenic peptides significantly reduces
the lag time and accelerates fibrillogenesis. Mechanistically
amyloidogenesis appears to be a nucleation-dependent process. Such
an event could conceivably account for relatively robust expansion
of amyloid deposition in vivo and thus constitute a central
event in the genesis of amyloid-related diseases. However, the
question that still remains unanswered is the conditions that might
affect nascent amyloid “nucleus” formation in vivo. Clearly,
both for the understanding of the biology of amyloidogenesis in
vivo and the development of therapeutic strategies, it is
essential to understand the conditions and identify the cellular
compartment(s) in which nascent amyloid fibrils are formed.
Pages 115-122
Shuguang Zhang, Sabina Janciauskiene (Communicated by Yuan Luo)
Multi-functional capability of proteins: alpha1-antichymotrypsin
and the correlation with Alzheimer’s disease
Abstract: An individual human is intrinsically capable of
performing multitasks, sometimes, one at a time and other times,
multiple at once. A talented musician can often play several
different instruments. A composer and conductor can not only play
several instruments, but he can also compose and conduct, for the
diverse activities. This multitask phenomenon is not likely limited
to human beings.
Pages 123-126
Kathy Cuc Nguyen, Jesusa L. Rosales, Milan Barboza, Ki-Young Lee (Communicated
by D. Allan Butterfield)
Controversies over p25 in Alzheimer’s disease
Abstract: Activity of the neuronal Cdc2-like kinase composed
of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, is
critical for the normal development of the central nervous system,
including cortical lamination and axonal patterning events.
Conversely, altered Cdk5 activity has been associated with several
neuronal defects including neurodegeneration. Indeed, an increasing
line of evidence suggests that Cdk5 contributes to neurodegeneration
in AD. For example, Cdk5 immunoreactivity is consistently detected
in neurofibrillary tangles (NFTs); Cdk5 phosphorylates tau and
promotes dimerization of tau to an AD-like state; sulfated
glycosaminoglycans co-exist with tau and Cdk5 in NFTs and remarkably
enhance tau phosphorylation by Cdk5; protein phosphatase 1 (PP1),
which shows decreased activity in AD brains, is inhibited by Cdk5
through phosphorylation of the PP1 inhibitor protein (I-1); in
primary neuronal cultures, Aß induces activation of Cdk5 that
results in tau hyperphosphorylation, cytoskeletal collapse, and cell
death. In addition, we and others have shown elevated Cdk5 activity
in mice
exhibiting tau hyperphosphorylation, and in AD brains. However, the
molecular mechanisms whereby Cdk5 activity is upregulated in AD
brain remain to be investigated.
Pages 127-128
Book Review: Aluminum and Alzheimer’s Disease. The Science
That Describes the Link. C. Exley (Ed), Elsevier, Amsterdam, 2001,
441 pp. Reviewed by Mark A. Lovell
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