| Volume 3, Number
5, October 2001
Pages 435-442
Lidström A-M, Hesse C, Rosengren L, Fredman P, Davidsson P, Blennow
K
Normal levels of clusterin in cerebrospinal fluid in Alzheimer’s
disease, and no change after acute ischemic stroke
Abstract: The protein clusterin has been suggested to be
involved in the pathogenesis of Alzheimer’s disease (AD). Its
expression is increased in brain regions affected by AD pathology,
and to elucidate if there is a concomitant increase of clusterin
also in the cerebrospinal fluid (CSF) in different neurological
disorders, CSF samples from patients with AD, vascular dementia (VAD),
Parkinson’s disease (PD), and controls were analysed. Also
longitudinal (five occasions) samples from patients with acute
stroke were analysed, to follow any degenerative/regenerative phase
after acute brain damage. However, there were no changes in
CSF-clusterin levels from patients in AD, VAD, PD or acute stroke,
as compared to controls. The increase of clusterin in brain tissue
is suggested to reflect a regenerative response process, which here
is shown not to be followed by a concomitant increase in the CSF.
Thus, CSF-clusterin can not be used as an indicator or a diagnostic
marker for AD.
Pages 443-451
Fernando Moreno-Herrero, José M. Valpuesta, Mar Pérez, Jaime
Colchero, Arturo M. Baró, Jesús Avila, Esteban Montejo de Garcini
Characterization by atomic force microscopy and cryoelectron
microscopy of tau polymers assembled in Alzheimer’s disease
Abstract: The structure of the Paired Helical filaments
(PHF)1, a polymer of the microtubule associated protein tau, has
been studied by Atomic Force Microscopy (AFM) and by cryoelectron
microscopy. Mica and graphite were used as substrates in the AFM
analysis with no differences in the results. A banding pattern of
8-12 nm width within the helical structure is found when detailed
analysis of the data is performed. High AFM resolution images
obtained by using an ultra sharp tip confirm the previous results
and suggest that the structures observed are compatible with a
helical ribbon made up of two parallel strands. These results were
confirmed by cryoelectron microscopy experiments.
Commentary on the Moreno-Herrero
et al. manuscript:
Page 453
George C. Ruben
Commentary
Pages 455-466
Warren J. Goux, Bingcam Liu, Abdurahman M. Shumburo, Samir Parikh
and Dennis R. Sparkman
A quantitative assessment of glycolipid and protein associated
with paired helical filament reparations from Alzheimer’s diseased
Brain
Abstract: Protease resistant paired helical filaments (prcPHF)
can be isolated from the brains of Alzheimer's diseased patients. A
second type of PHF, A68 PHF, may be extracted in soluble form from
brain homogenate and induced to form filaments in vitro. Here we
use a variety of analytical techniques to assess the protein,
carbohydrate and fatty acid composition of prcPHF and A68 PHF.
High-field 1H NMR of both PHF preparations display similar fatty
acid and carbohydrate proton resonances, consistent with the
presence of a structurally similar glycolipid. Carbohydrate analysis
showed that both preparations contained greater than 82% glucose,
with the remainder consisting of less than 12% mannose or galactose.
While the relative abundance of C16:1 was significantly lower in A68
PHF than in prcPHF, both preparations contained otherwise similar
fatty acid profiles with the most abundant lipid component being
oleic acid (C18:1, 29.3+9.0%) followed by palmitic (C16:0,
28.5+5.6%) and stearic acids (C18:0, 17.6+7.5%). Amino acid
analysis of the prcPHF and the A68 PHF preparations revealed a
profile reasonably consistent with that previously determined for
PHF-tau but significantly higher in glycine and lower in lysine than
would be predicted from the cDNA sequence. On a weight per cent
basis, protein accounted for about 51% of the A68 PHF samples but
only about 10% of the prcPHF samples. Carbohydrate and fatty acid
accounted for about 39% and 9% of the A68 PHF samples but 74% and
16% of the prcPHF samples. Both PHF preparations showed strong
correlations between the total amount of tau protein and fatty acid.
These results suggest that a glycolipid component forms an integral
part of the PHF structure.
Commentary on the Goux et al.
manuscript:
Pages 467-469
Shu G. Chen
Molecular profiling of paired helical filaments
Pages 471-477
J. R.Connor, E. A. Milward, S. Moalem, M. Sampietro, P. Boyer, M.
E.Percy, C. Vergani, R. J. Scott, M. Chorney (communicated by
Paolo Zatta)
Is hemochromatosis a risk factor for Alzheimer’s disease?
Abstract: Excess iron accumulation in the brain is a
consistent observation in Alzheimer's Disease. Iron affects amyloid
precursor protein (AßPP) processing and promotes deposition of Aß.
Iron is also among the most potent biological toxins because of its
ability to react with oxygen to form reactive oxygen species.
Consequently, elucidation of the mechanisms associated with
maintaining brain iron homeostasis is fundamentally important to
understanding the underlying pathogenesis in AD. The iron overload
disorder, Hemochromatosis, is the most common genetic disorder
(1:200) so a significant percentage of AD patients can be expected
to carry this mutation. Heterozygotes for this mutation also have
an increased, but sub-clinical iron burden. Given the high
percentage of the population who are at significant risk for iron
overload, we propose that the hemochromatosis mutation be considered
as a confounding factor when evaluating the contribution of genetic
associations with AD and treatment strategies and efficacy. Two
recent papers and new evidence presented here that the protein
associated with hemochromatosis is expressed on blood vessels,
choroid plexus and the ependymal cells in the brain are offered as
support for this proposal.
Pages 479-483
Rebecca Ho, Daniela Ortiz, Thomas B. Shea (communicated by Garth
Hall)
Amyloid-beta promotes calcium influx and neurodegeneration via
stimulation of L voltage-sensitive calcium channels rather than NMDA
channels in cultured neurons
Abstract: Exposure of cultured neurons and neuronal cells to
aggregated amyloid-beta (Aß) induces multiple neurodegenerative
events including accumulation of cytosolic calcium, generation of
reactive oxygen species, abnormal levels of phosphorylation of the
microtubule-associated protein tau, and apoptosis. Prevention of
accumulation of calcium within the cytosol also prevents all other
events, suggesting that calcium accumulation is an early and pivotal
event in Aß neurotoxicity. Calcium influx has been suggested to
occur via L voltage-sensitive calcium channels or NMDA channels.
Calcium influx into differentiated human neuroblastoma cells has
been previously attributed to the L voltage-sensitive calcium
channel, but the contribution of the NMDA channel was not examined.
In the present study, treatment of these cells with MK-801, an
antagonist of NMDA channels, failed to attenuate Aß-induced calcium
influx or neurodegeneration, while nimopridine, an antagonist of the
L voltage-sensitive calcium channel, blocked Aß-induced calcium
influx. Our findings suggest that NMDA channels do not contribute
significantly to Aß neurotoxicity in these acute cell culture
analyses.
Pages 485-494
Yu Xia, Tsunao Saitoh, Kenji Uéda, Seigo Tanaka, Xiaohua Chen,
Makoto Hashimoto, Leigh Hsu, Chris Conrad, Mary Sundsmo, Makoto
Yoshimoto, Leon Thal, Robert Katzman, Eliezer Masliah
Characterization of the human NACP/alpha-Synuclein (SNCA) gene:
genomic structure, transcription start site, promoter region and
polymorphisms
Abstract: The human NACP/alpha-synuclein (SNCA) gene has been
cloned. This gene consists of 6 exons ranging in size from 42 to
1110bp. The translation start codon ATG is encoded by exon 2 and
the stop codon TAA is encoded by exon 6. The non-Aß component of
Alzheimer’s disease amyloid (NAC) is encoded by exon 4. The two
previously reported minor isoforms of NACP/alpha-synuclein, NACP112
(29) and NACP126 (6), are alternatively spliced products, in which
exon 5 and exon 3 are spliced out, respectively. Exon 1 was found
to have different splicing sites, producing different
5'-untranslated sequences in the cDNAs. A previously reported
dinucleotide repeat polymorphic marker has been mapped to 8kb
upstream of the transcription start site. A highly TC-rich sequence
in intron 4 was found to be polymorphic by length and four alleles,
A0, A1, A2 and B have been identified in the Caucasian population.
Genotyping this polymorphism among pure Alzheimer’s, Lewy body
variant and Parkinson's subjects and aged normal control subjects
did not reveal any significant differences.
Pages 495-505
Stephen W. Scheff and Douglas A. Price
Alzheimer’s disease-related synapse loss in the cingulate cortex
Abstract: Synapse loss is considered a profound
neuropathology associated with Alzheimer’s disease (AD). This
AD-related change in connectivity can be demonstrated in many
regions of the neocortex. The posterior cingulate cortex has been
identified as an area involved early in the disease process but has
not been well studied. The anterior cingulate cortex, which is
morphologically distinct from the posterior cingulate, is also
involved in AD. The present study employed ultrastructural
techniques to assess synaptic numbers in these two regions of
association cortex. Both cingulate areas demonstrated a significant
loss in lamina III in AD, while only the posterior cingulate
manifested a loss in lamina V. The failure to find a significant
change in lamina V of the anterior cingulate may be related to its
connectivity with the motor system. The heterogeneity of synaptic
change in this cortical region may reflect important information
concerning corticocortico connectivity changes in AD.
Pages 507-516
H. Feldman, R. Gabathuler, M. Kennard, J. Nurminen, D. Levy, S. Foti,
D. Foti, B.L Beattie, W.A. Jefferies (Communicated by David
Small)
Serum p97 levels as an aid to identifying Alzheimer's disease
Abstract: Background: The application of formal clinical
diagnostic criteria for the identification of Alzheimer’s Disease
(AD) has improved diagnostic sensitivity. However, there remains a
need for non-invasive biological markers and laboratory tests, which
can facilitate case identification, and the assessment of treatment
response. The p97 protein is a secreted protein specifically
expressed by amyloid plaque associated reactive microglia that may
have AD diagnostic ability. Methods: A quantitative
radioimmunoassay was developed to measure serum p97. This study,
under a double blind protocol, evaluated the utility of serum p97 as
diagnostic test for AD. All subjects were referred to the UBC Clinic
for Alzheimer’s Disease and Related Disorders (CADRD) for clinical
assessment of dementia. A serum p97 sample was obtained at the time
of assessment but diagnosis of disease was determined independently
of p97 examination. Results: “Possible” and “probable” AD cases (n
= 41) and cognitively normal controls (n = 64) showed a highly
significant difference in mean p97 concentration (41 vs. 20 ng/ml,
p<0.001). There was some overlap in p97 distributions between AD
cases and control subjects. The area under the curve (AUC) for the
receiver operator curve (ROC) was 0.812. Conclusions: These results
further support the specificity of high serum p97 levels in AD and
its potential utility as a biological marker in AD. The reproducible
elevation of serum p97 in AD underlines the need to further
determine its role as a biological marker and diagnostic adjunct for
AD.
Page 517
Book Review: Special Care Units: Research and Practice in
Alzheimer’s Disease, Holmes D, Teresi JA, Ory M (Eds), Serdi
Publisher, Paris, France, 2000, 272 pp. Reviewed by Carlos Garcia
Page 519
Book Review: Alzheimer's Disease: A Compendium of Current
Theories, Annals of the New York Academy of Sciences, Volume 924.
Zaven S. Khachaturian and M. Marsel Mesulam (Eds), The New York
Academy of Sciences, New York, 2000, 190 pp. Reviewed by Marcelle
Morrison-Bogorad
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