| Volume 5, Number
1, February 2003
Pages 1-8
Hone E, Martins IJ, Fonte J, Martins RN
Apolipoprotein E Influences Amyloid-beta Clearance from the
Murine Periphery
Abstract: The relationship between amyloid-ß protein (Aß)
metabolism and Alzheimer’s disease is currently poorly understood.
While it is well known that the generation of Aß results from
enzymatic cleavage of its parent molecule, the amyloid ß protein
precursor (AßPP), there is little information available regarding
its in vivo clearance. The E4 isoform of apolipoprotein E (apoE)
has been associated with poor clearance of Aß under in vitro
conditions. This is thought to be due to its poor ability to bind
Aß compared with the other common isoforms, apoE2 and apoE3.
Although cell culture studies support the notion that Aß clearance
depends upon apoE isoform, validation of these findings requires Aß
clearance studies in vivo. In this study, we examined the
clearance of Aß in vivo from the periphery in mice that
expressed apoE (C57BL/6J) or lacked apoE (APOE knockout). We
measured the clearance of peripherally injected Aß over time and
additionally, the quantities sequestered by peripheral organs.
Western blot analysis of the murine plasma indicated that the
half-life of Aß in the periphery was approximately 15 minutes. The
livers of the C57BL/6J mice were found to have sequestered
approximately 40% of the total injected Aß at 90 minutes
post-injection, whilst their kidneys contained 5% of the total
injected Aß. In contrast, the livers and kidneys of the APOE
knockout animals were found to contain no detectable Aß.
These findings indicate that Aß is rapidly removed from the plasma
by murine peripheral tissues and the rate of its clearance is
affected by apoE.
Pages 9-14
Thomas B. Shea, Eugene Rogers, David Ashline, Daniela Ortiz, Nancy
Duarte, Thomas O. Wilson, Robert J. Nicolosi, Min-Shyan Sheu
Vitamin E deficiency does not induce compensatory antioxidant
increases in central nervous system tissue of apolipoprotein
E-deficient mice
Abstract: Compensatory upregulation in endogenous
antioxidants has been shown to accompany certain genetic and dietary
deficiencies that promote oxidative stress, including that related
to Alzheimer’s disease. We compared antioxidant levels in brain
tissue of normal and transgenic mice lacking apolipoprotein E
following dietary deprivation of vitamin E or folate. As described
previously, ApoE-deficient mice displayed increased levels of the
endogenous antioxidant glutathione as compared to normal mice, and
increased these levels further following folate deprivation. By
contrast, glutathione was depleted following vitamin E deprivation
in brain tissue of normal and ApoE-deficient mice. TBAR analyses
confirmed increased oxidative damage following vitamin E
deprivation. However, combined deprivation of folate and vitamin E
resulted in levels of glutathione intermediate between those
observed following deprivation of either agent, indicating that the
lack of compensatory increase in glutathione following vitamin E
deprivation was not due to overt neurotoxicity. Similar results
were observed for total antioxidant levels in brain tissue. The
differential response to vitamin E and folate deprivation is
consistent with the possibility that specific differences in
oxidative damage may result from deficiencies in either of these
agents. The lack of a compensatory response to vitamin E
deprivation highlights the importance of dietary vitamin E in
prevention of chronic neurodegeneration.
Pages 15-23
Ravi Shankar Mishra, Sharmila Bose, Yaping Gu, Ruliang Li, Neena
Singh
Aggresome formation by mutant prion proteins: the unfolding role
of proteasomes in familial prion disorders
Abstract: Although familial prion disorders are a direct
consequence of mutations in the prion protein gene, the underlying
mechanisms leading to neurodegeneration remain unclear. Potential
pathogenic mechanisms include abnormal cellular metabolism of the
mutant prion protein (PrPM), or destabilization of PrPM structure
inducing a change in its conformation to the pathogenic PrP-scrapie
(PrPSc) form. To further clarify these mechanisms, we investigated
the biogenesis of mutant PrP V203I and E211Q associated with
Creutzfeldt-Jakob disease, and PrP Q212P associated with
Gerstmann-Straussler-Scheinker syndrome in neuroblastoma cells. We
report that all three PrPM forms accumulate similarly in the cytosol
in response to proteasomal inhibition, and finally assemble as
classical aggresomes. Since the three PrPM forms tested in this
report are distinct, we propose that sequestration of misfolded PrPM
into aggresomes is likely a general response of the cellular quality
control that is not specific to a particular mutation in PrP.
Moreover, since PrP has the remarkable ability to refold into PrPSc
that can subsequently replicate, PrPM sequestered in aggresomes may
cause neurotoxicity by both direct and indirect pathways; directly
through PrPSc aggregates, and indirectly by depleting normal PrP,
through induction of a cellular stress response, or by other
undefined pathways. By contrast, sequestered PrPM may be relatively
inert, and cellular toxicity may be mediated by early intermediates
in aggresome formation. Taken together, these observations
demonstrate the role of proteasomes in the pathogenesis of familial
prion disorders, and argue for further explanation of its
mechanistic details.
Pages 25-30
Jovana Gasic-Milenkovic, Claudia Loske, Gerald Münch
Advanced glycation endproducts cause lipid peroxidation in the
human neuronal cell line SH-SY5Y
Abstract: Advanced glycation endproducts (AGEs),
sugar-derived protein modifications and lipid peroxidation products
are prominent features of Alzheimer’s disease. AGEs accumulate on
ß-amyloid plaques during the course of the disease and can exert
chronic oxidative stress via receptor-mediated mechanisms. Lipid
peroxidation products such as hydroxynonenal, further markers of
oxidative stress, are also increased in Alzheimer’s diesease. In
this study we present evidence for a direct biochemical link between
AGEs and lipid peroxidation. Our results show that AGEs induce lipid
peroxidation in a neuronal cell line in a dose-dependant manner,
and that blocking the specific AGE-receptor RAGE, as well as using
different antioxidants (a-lipoic acid, N-acetylcysteine,
17ß-estradiol or aminoguanidine) can reduce the AGE-mediated
formation of lipid peroxidation products. Thus, both RAGE
antagonists and scavengers of oxygen free radicals could be useful
in protecting brain tissue from lipid peroxidation and its
pathophysilogical consequences that occur in Alzheimer’s disease.
Pages 31-38
Angelica Becaria, Stephen C. Bondy, Arezoo Campbell
Aluminum and Copper interact in the Promotion of Oxidative but
not Inflammatory events: Implications for Alzheimer’s Disease
Abstract: The etiology of Alzheimer’s Disease (AD) is
multifactorial. It has been suggested that transition metals such
as copper (Cu) and iron (Fe) as well as aluminum (Al) may be
involved in the pathogenesis of the disorder. While Cu and Fe are
redox-active, Al only exists in the trivalent form and is redox-inert.
We previously demonstrated that Al exposure causes an increase in
inflammatory parameters in human glioblastoma T98G cells. In the
present study we further demonstrate that co-exposure with Cu
exacerbates the oxidative but not inflammatory effects of Al in this
cell line. While Cu-induced reactive oxygen species (ROS)
production was greatly enhanced in the presence of Al, TNF-alpha
secretion induced by either metal was not further potentiated by
simultaneous exposure to Al and Cu. Furthermore, exposure to both
metals reduced the individual Al and Cu-induced activation of the
immune-related transcription factor NF-kappaB. Therefore, while
synergistic interaction between the two metals increases oxidative
events, this does not lead to potentiation of Al-induced
inflammation. Thus the ability of aluminum to promote inflammatory
processes does not depend on an increase ROS production induced by
interaction with transition metals.
Pages 39-48
Milos D. Ikonomovic, Elliott J. Mufson, Joanne Wuu, Elizabeth J.
Cochran, David A. Bennett, Steven T. DeKosky
Cholinergic plasticity in hippocampus of individuals with
mild cognitive impairment: correlation with Alzheimer's
neuropathology
Abstract: Several recent studies indicate that activity of
cholinergic enzymes in the cortex of people with mild cognitive
impairment (MCI) and early Alzheimer's disease (AD) are preserved.
We correlated levels of hippocampal choline acetyltransferase (ChAT)
activity with the extent of AD lesions in subjects from the
Religious Order Study, including cases with no cognitive impairment
(NCI), MCI, and with mild to moderate AD. Hippocampal ChAT activity
levels were also determined in a group of end-stage AD patients who
were enrolled in the University of Pittsburgh Alzheimer’s Disease
Research Center. MCI subjects were characterized with increased
hippocampal ChAT activity. This elevation was no longer present in
mild AD cases, which were not different from NCI subjects. Severe AD
cases showed markedly depleted hippocampal ChAT levels. In NCI, MCI,
and mild-moderate AD, there was a positive correlation between
hippocampal ChAT activity levels and progression of neuritic plaque
pathology in entorhinal cortex and hippocampus. A significant
elevation of hippocampal ChAT in the MCI group was found selectively
in the limbic (i.e., entorhinal-hippocampal, III/IV) Braak stages.
We hypothesize that cholinergic changes in the hippocampus of MCI
subjects reflect a compensatory response to the progressive
denervation of the hippocampus by lost entorhinal cortex input.
Moreover, the present findings suggest that the short-term memory
loss observed in MCI is not caused by cholinergic deficits; it more
likely relates to disrupted entorhinal-hippocampal connectivity.
Pages 49-56
Dejan V.Micic, Natasa D. Petronijevic and Svetlana S.Vucetic
Superoxide dismutase activity in the Mongolian gerbil brain
after acute poisoning with aluminum
Abstract: In this study, the activity of total superoxide
dismutase was investigated in brains of adult Mongolian gerbils (Meriones
unguiculatus) treated with aluminum. AlCl3x6H20, was given “per os”
in the amount of 3,7g/kg body weight. Animals were killed 24, 48, 72
and 96 hours after the treatment and SOD activity was measured in
crude mitochondrial fractions of cortex, thalamus and hippocampus.
The SOD activity was significantly elevated in all investigated
brain regions 24 hours after aluminum administration. The most
prominent increases (up to 200% of values in control animals) were
detected in thalamus and hippocampus, whereas the activity was 165%
of control value in the cortex. The SOD activity returned to control
values in all regions investigated forty-eight hours after
poisoning. A slight secondary increases in SOD activity were
observed at 72 hours, reaching 171%, 148%, and 166 % of control
values in the thalamus, hippocampus and cortex, respectively, 96
hours after AlCl3x6H20 administration. We conclude that Al
administration causes a biphasic stimulation of SOD activity in
various brain regions over 96 hours, providing evidence that
oxidative stress is involved in aluminum toxicity to the brain.
Pages 57-63
Marwan N. Sabbagh, Nina Silverberg, Bashar Majeed, Shefali Samant,
D. Larry Sparks, James Seward, Donald J. Connor
Length Of Stay In Skilled Nursing Facilities Is Longer For
Patients With Dementia
Abstract: Studies estimate prolonged stays in acute and
sub-acute facilities for patients with dementia. Actuarial
projections suggest prolonged stays in long term care facilities for
patients with dementia. To test these predictions, we assessed
whether patients with dementia stay in skilled nursing facilities (SNF)
longer than patients without dementia. We obtained medical records
of 5,373 residents discharged from a SNF between 1996 and 2001.
Residents were identified as having dementia by ICD-9 codes. Age,
sex and length of stay (LOS), measured in days from admission to
discharge or death, were gathered. Mean LOS for patients with
dementia (92.7 ± 313.0, n=758) was significantly longer than
non-demented patients (29.7 ± 136.8, n=4615, p<0.001). In a subset
of individuals who stayed until death, the mean LOS for patients
with dementia (202.9 ± 528.6, n=195) also was significantly longer
than for non-demented patients (91.8 ± 300.5, n=610, p<0.001). LOS
was increased for demented patients even within age groups. Thus,
patients with dementia stay in SNFs significantly longer from entry
until discharge or death. It is likely that demented patients enter
for non-physical, cognitive related reasons. These results may help
families and institutions plan for long-term care.
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