| Volume 5, Number 6, December
2003
Pages 423-427
Pamela Zambenedetti,
GianLuca De Bellis, Ida Biunno, Massimo Musicco, Paolo Zatta
Transferrin C2 Variant Does Confer a Risk for Alzheimer's
disease in Caucasians
Abstract: Several gene mutations are associated with an
increased risk of Alzheimer’s disease. Previous studies reported
higher transferrin C2 allele frequencies in Alzheimer’s disease
compared with normal controls. However, potential interactions
between transferrin C2 and APOE (epsilon4), have not been
extensively investigated and have been the subject of controversial
reports from several laboratories. We have carried out a
case-control study on the association between Alzheimer’s disease
and transferrin C2 and APOE epsilon4 alleles. Epsilon4 allele was
associated with a four fold increase in the risk of disease, and
transferrin C2 allele was significantly associated with Alzheimer’s
disease only in epsilon4 negative subjects. These results suggest
that apoE and transferrin may be part of a complex mechanism in the
pathogenesis of Alzheimer’s disease.
Pages 429-436
Richard T. Reid and
Marwan N. Sabbagh
Effects of Donepezil Treatment on Rat Nicotinic Acetylcholine
Receptor Levels In Vivo and In Vitro
Abstract: Research on acetylcholinesterase inhibitors (ChEIs)
indicates that long term exposure increases the level of nicotinic
acetylcholine receptors (nAChRs) but the effects of donepezil on
nAChRs are not well studied. Therefore, we investigated the effects
of sub-chronic donepezil administration on nAChRs in rats and rat
pheochromocytoma PC-12 cells. Male Sprague Dawley rats were
administered donepezil (0.7 and 2.4 µmoles/kg), nicotine (2.5
µmoles/kg) or saline subcutaneously twice daily for 14 days, PC-12
cells were incubated with 10-6 to 10-4 M donepezil for 72 hours and
nAChR levels were determined by receptor binding assay using the
nAChR ligands [3H]-epibatidine (EPI) for non-alpha7 nAChRs and
[3H]-methyllyconitine (MLA) for alpha7 nAChRs. Chronic donepezil
administration at 1.4 µmoles/kg/day and 4.8 µmoles/ kg/day
significantly increased [3H]-epibatidine binding in the cortex to
126+/-1.3% and 127+/-3.2% of the saline control animals,
respectively. [3H]-MLA binding in the cortex increased to 114+/-4.4
% and 124+/-2.8% of the control group for the high and low dose
groups, respectively. Hippocampal [3H]-EPI binding in the low dose
and high dose groups significantly increased to 135+/-3.6% and
125+/-4.6% of the controls, respectively while there were no changes
in the level of [3H]-MLA binding. In striatal homogenates, neither
[3H]-EPI nor [3H]-MLA binding were significantly effected at either
dose of donepezil. In PC-12 cells, [3H]-EPI binding was increased at
the non-physiological 10-4M concentration only. There was no effect
of donepezil on [3H]-MLA binding at any concentration examined.
These results indicate that donepezil increases cortical alpha7 and
non-alpha7 nAChRs, hippocampal non-alpha7 nAChRs but does not
influence striatal nAChR levels. Furthermore, the lack of an effect
on the alpha7-nAChRs in PC-12 cells suggests that the increase in
cortical alpha7 nAChRs may be an indirect effect of increased
acetylcholine levels in vivo.
Pages 437-444
Patrizia Fattoretti,
Bertoni-Freddari Carlo, Marta Balietti, Eugenio Mocchegiani, Janez Scancar,
Pamela Zambenedetti, Paolo Zatta
The effect of chronic aluminum(III) administration on the
nervous system of aged rats: clues to understand its suggested role
in Alzheimer’s disease
Abstract: The effect of chronic aluminum intake has been
investigated in the brain of aged male Wistar rats to assess the
potential role of the accumulation of this metal ion on the
development of neurodegenerative features observed in Alzheimer’s
disease. AlCl3 x 6 H2O (2g/L) was administered to experimental
animals for 6 months in the drinking water. The total content of Al
(ug/g fresh tissue) was measured by inductively coupled plasma
atomic emission spectrometry (ICP-AES), while the content of Cu, Zn
and Mn was determined by flame AAS in the prosencephalon +
mesencephalon, pons-medulla and cerebellum of control and
A(III)-treated animals. The area occupied by mossy fibres in the CA3
field of the hippocampus was estimated by a computer-assisted
morphometric method following Timm’s preferential staining. In
Al(III)-treated rats the concentration of Cu, Zn and Mn did not
increase significantly (p<0.5) in prosencephalon + mesencephalon,
nor in pons-medulla (p<0.5) except for Cu (p<0.05) in pons-medulla.
In the cerebellum the only significant increase was seen for Zn
(p<0.01) while no change was observed for Cu and Mn. The area
occupied by the mossy fibres in the hippocampal CA3 field was
significantly increased (+32%) in aged Al(III)-treated rats. Since
Cu, Zn and Mn are essential components of the cytosolic and
mitochondrial superoxide dismutases, it is possible that the
increased content of these ions in aged Al(III)-treated rats
represents an increased amount of genetic expression of these
antioxidant enzymes. Considering that the positivity to Timm’s
reaction is based on the presence of free or loosely bound Zn2+ ions
within synaptic terminals and that Zn2+ ions are reported to be
accumulated by hippocampal neurons when tissue injury occurs, the
increased area of the mossy fibres in CA3 field of Al(III)-treated
rats could indicate increased hippocampal damage in these animals.
Taken together, the present findings indicate that the aging CNS is
particularly susceptible to Al(III) toxic effects which may increase
the cell load of oxidative stress and may contribute, as an
aggravating factor, to the development of neurodegenerative events
as observed in Alzheimer’s disease.
Pages 445-454
Isidro Ferrer, Isabel
Hernández, Berta Puig, María Jesús Rey, Mario Ezquerra, Merce Boada
Ubiquitin-negative mini-Pick-like bodies in the dentate gyrus in
P301L tauopathy
Abstract: Neuropathological and biochemical findings are
reported in a patient who had suffered from frontotemporal dementia
associated with a P310L mutation in the tau gene and included in the
H1 haplotype. Tau accumulation, as revealed with phospho-specific
anti-tau antibodies Thr181, Ser199, Ser202, Ser214, Ser262, Ser396,
Ser422 and AT8 (Ser202 and Thr205), was found in neurons with
pre-tangles, and astrocytes and oligodendrocytes through the brain.
The most characteristic feature was tau immunoreactivity decorating
the perinuclear region and small cytoplasmic aggregates designed as
mini-Pick-like bodies, mainly in the dentate gyrus. Inclusions were
not stained with anti-ubiquitin antibodies and did not recruit
tubulins. Tau accumulation in individual cells was associated with
increased expression of kinases linked with tau phosphorylation,
mainly active (phosphorylated) stress kinases SAPK/JNK and p38
(SAPK/JNK-P and p38-P). Phosphorylated GSK-3ß at Ser9 (GSK-3ß-P),
that inactivates the kinase, was particularly abundant in
mini-Pick-like bodies, thus suggesting alternative roles of GSK-3
probably involved in cell survival. Western blots of
sarkosyl-insoluble fractions revealed a double band pattern of
phospho-tau of 68/66 kDa and 64 kDa in the hippocampus and white
matter in the P310L mutation. Sarkosyl-insoluble fractions of the
hippocampus were enriched in p38-P and GSK-3ß-P in Alzheimer’s
disease (AD) cases, processed in parallel for comparative purposes,
but not in the P310L mutation. In addition, no bands of high
molecular weight were found in P310L in contrast with AD in these
fractions. These findings indicate that the major sites of tau
phosphorylation, and the expression of kinases involved in tau
phosphorylation are active in P310L mutation as in AD and other
tauopathies. Yet the P310L mutation has particular phospho-tau
inclusions that are not tag with ubiquitin and appear to be rather
soluble when compared with AD.
Pages 455-462
Stephanie A. Lahousse,
Edward G. Stopa, Andrew E. Mulberg, and Suzanne M. de la Monte
Reduced Expression of the Cystic Fibrosis Transmembrane Conductance
Regulator Gene in the Hypothalamus of Patients with Alzheimer’s
Disease
Abstract: Background: The cystic fibrosis transmembrane
conductance regulator (CFTR) gene encodes a ~150-165 kD glycoprotein
that is mutated in individuals with cystic fibrosis. Previous
studies demonstrated expression of the CFTR gene in the
hypothalamus, suggesting a potential role for this molecule in the
regulation of systemic metabolic functions. Individuals with cystic
fibrosis often exhibit wasting and marked reductions in body fat
content. Since the hypothalamus is a late target of
neurodegeneration in Alzheimer’s disease (AD), we postulated that
patients with end-stage AD and bodily wasting would have reduced
levels of CFTR expression in the hypothalamus. Methods: CFTR mRNA
and protein were examined in postmortem hypothalamic tissue from 11
AD and 7 aged controls using in situ hybridization and
immunohistochemical staining. Standardized sections that included
the supra-optic, paraventricular, anterior, and ventromedial nuclei,
and the lateral hypothalamus were studied. Results: The density of
CFTR+ neurons and the intensity of the CFTR hybridization signals
were strikingly reduced in AD. Immunohistochemical staining studies
demonstrated CFTR immunoreactivity most prominently distributed in
small clusters of neurites (5 to 20 in number). Digital image
quantification showed that the density of CFTR+ neurites was
significantly reduced in AD relative to aged control samples
(P=0.001). However, there was no evidence for selective involvement
of particular hypothalamic nuclei. Conclusions: CFTR gene expression
is down-regulated and its corresponding immunoreactivity reduced in
AD relative to control hypothalamic tissue. Reduced CFTR expression
in the hypothalamus may represent an important mechanism by which AD
neurodegeneration contributes to body wasting in the late stages of
disease.
Pages 463-465
Thomas A. Ala, Michael
D. Mattson, William H. Frey, II (Communicated by
Laura Fratiglioni)
The clinical diagnosis of Alzheimer's disease without the use of
head imaging studies. A cliniconeuropathological study
Abstract: Although head imaging studies are frequently used
in the work-up of dementia, published criteria for the clinical
diagnosis of Alzheimer's disease (AD) do not require them. Since our
brain bank contains cases in which physicians had specifically
diagnosed AD without using a head imaging study, we thought it of
interest to investigate the accuracy of their clinical diagnoses. We
retrospectively reviewed 911 consecutive dementia cases for those
clinically diagnosed as either AD or senile dementia (SD).
Twenty-one were identified in which head imaging studies had not
been used, each diagnosed as AD or SD by a different physician. In
only three had the physician reported a reason why a study was not
done. In all 21 cases the primary neuropathological cause of the
dementia was AD. Neuropathology in addition to AD was also noted,
including cortical Lewy bodies in three, infarcts on gross
examination in three, multiple microscopic infarcts in four, and
multiple cerebral metastases in one. Acknowledging a number of study
limitations, it is remarkable that the judgment of the physicians
was correct regarding AD in all 21 cases. It is questionable if a
head CT or MRI scan at time of diagnosis would have benefited any of
the patients.
Pages 467-476
Randall L. Woltjer,
Izumi Maezawa, Joyce J. Ou, Kathleen S. Montine, Thomas J. Montine
Advanced glycation endproduct precursor alters intracellular
amyloid- ß/AßPP carboxy-terminal fragment aggregation and
cytotoxicity
Abstract: Carbonyl stress from products of lipid
peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars
in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G),
may contribute to neurodegeneration in Alzheimer’s disease (AD). We
tested the hypothesis that these carbonyls alter the proposed
central pathogenic mechanism of AD, intracellular amyloid-ß
(Aß)-mediated cytotoxicity, using a human neuroblastoma cell line
that conditionally expresses Aß40 and other carboxy-terminal
fragments (CTFs) of the amyloid precursor protein. HNE was a potent
cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each
was independent of Aß/CTF expression and not altered by
alpha-tocopherol. In contrast, MG cytotoxicity was enhanced by the
induced expression of Aß/CTFs and suppressed by alpha-tocopherol.
Alpha-tocopherol cytoprotection was accompanied by decreased Aß/CTF
aggregation. G also promoted Aß/CTF aggregation but by mechanisms
unaffected by alpha-tocopherol treatment. Our findings showed that
Aß/CTF aggregation and cytotoxicity may be profoundly altered by
aldehydes associated with diabetes and that in the case of MG, this
process is suppressed by alpha-tocopherol. Moreover, our results
suggest that while intracellular aggregation of Aß/CTFs may be
necessary for the development of toxicity attributable to their
expression in this model, the presence of high-molecular weight
aggregated Aß/CTFs does not invariably lead to cytotoxicity.
Pages 477-478
Joseph Martin Alisky
Letter to the Editor: A Case History Illustrating How
Extended Release Cholinesterase Inhibitors Could Improve Management
of Alzheimer’s Disease
Pages 479-480
Hernando Rafael
Letter to the Editor: Cerebral Atherosclerosis And Oxidative
Stress In Alzheimer’s Disease
Pages 481-482
Suzanne de la Monte
In reply to Rafael letter
Pages 483-489
Transcript of Live
Discussion held at the
Alzheimer Research Forum
From Here to There: AßPP as an Axonal Transport Receptor --
How Could This Explain Neurodegeneration in AD?
Pages 491-497
Transcript of Live
Discussion held at the
Alzheimer Research Forum
Amyloid-ß Degradation: The Forgotten Half of Alzheimer's
Disease
Page 499
Book Review:
Methods in Molecular Biology, Volume 232, Protein Misfolding and Disease:
Principles and Protocols. Edited by Peter Bross and Niels Gregersen. Humana
Press, Totowa, New Jersey, 2003, 318pp. Reviewed by Jing Zhang.
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