| Volume 3, Number
6, December 2001
Pages 521-523
George Perry, Bethany S. Kumar, and Mark A. Smith
Editorial: Journal Of Alzheimer’s Disease Established as a
Leading Journal
Pages 525-529
Sirikarnt Dhitavat, Eugene Rogers and Thomas B. Shea
Differential efficacy of lipophilic and cytosolic antioxidants on
generation of reactive oxygen species by amyloid-beta
Abstract: Exposure of neurons to amyloid-beta (Aß) is
accompanied by a cascade of oxidative damage that initiates with
lipid peroxidation followed by subsequent generation of cytosolic
free radicals and reactive oxygen species (ROS). The antioxidant
vitamin E has been utilized to counteract Aß-induced oxidative
stress. We considered herein whether or not the lipid-solubility of
vitamin E limits its neuroprotection to membrane-related oxidative
damage, and renders it relatively ineffective where prior lipid
peroxidation has already generated cytosolic free radicals and ROS.
To test this possibility, we treated differentiated SH-SY-5Y human
neuroblastoma with vitamin E or a cell-permeant antioxidant,
N-acetyl cysteine (NAC), simultaneously with or 15 min after the
application of Aß. Both vitamin E and NAC prevented Aß-induced ROS
generation when applied simultaneously with Aß, but only NAC
prevented Aß-induced ROS generation when added to cultures that had
previously been exposed to Aß. These results support the hypothesis
that vitamin E can quench Aß-induced lipid peroxidation, but cannot
effectively quench ROS generated by prior lipid peroxidation. These
findings in cell culture may provide limited insight into why
vitamin E is not fully effective against neurodegeneration in AD in
clinical settings, since some neuronal populations are likely to
already have been compromised by prior Aß exposure before vitamin E
treatment was initiated.
Pages 531-539
Jignesh D. Pandya, Kunjan R. Dave, Surendra S. Katyare
Effect of long-term aluminum feeding on lipid/phospholipid
profiles of rat brain synaptic plasma membranes and microsomes
Abstract: Long-term exposure to AlCl3 resulted in 57%
decrease in the total phospholipid (TPL) content of synaptic plasma
membranes from rat brain with significant decrease in the proportion
and content of most of the phospholipid classes (32%-77% decrease);
the extent of decreases was of lesser magnitude for
phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The
microsomal TPL and CHL content decreased by 74% and 35% with
marginal changes in the phospholipid composition. However, the
contents of all phospholipids decreased uniformly by about 70%. The
synaptic plasma membranes were more fluidized in Al fed rats. The
results suggest that long- term exposure of rats to Al can alter the
structure/function of synaptic plasma membranes and microsomes.
Pages 541-549
Erik T. Jansson
Aluminum exposure and Alzheimer’s disease
Abstract: The regulatory agencies of the United States and
Canada have placed aluminum on priority lists for research designed
to fill data gaps relating to neurotoxicity. This is to create a
factual basis for the establishment of health standards for drinking
water. In this review, we consider evidence for a significant role
for aluminum in AD. Aluminum has been implicated as a potential
risk factor in Alzheimer’s Disease (AD) and for elderly cognitive
impairment by epidemiology studies of drinking water and a food
study. Most people experience aluminum brain overload in the aging
process. Aluminum levels over 20 times higher than those of a
middle-aged group were found in a brain autopsy study of elderly
persons, roughly correlating over the age period with densities of
senile plaques and neurofibrillary tangles. Persons with AD have
been found to experience increased absorption of aluminum and higher
blood levels. More controversially, the majority of brain studies
also show elevated aluminum levels, though there is disagreement
over location of metal buildup. Clinical intervention to lower
brain aluminum by chelation has slowed the progression of AD.
Commentary on the Jansson
manuscript:
Pages 551-552
Christopher Exley
Aluminium and Alzheimer’s Disease
Pages 553-562
Maria Cristina Polidori, Giuseppe Menculini, Umberto Senin, Patrizia
Mecocci (communicated by James Geddes)
Review: Dementia, depression and parkinsonism: a frequent
association in the elderly
Abstract: Depression and parkinsonism constitute two frequent
findings in elderly demented patients. A large body of research,
including epidemiological, retrospective, and prospective studies
have contributed to the understanding of complex and common
situations in the elderly, in which depression, parkinsonian signs,
and cognitive impairment coexist. Many aspects regarding the
“associated syndromes of dementia”, however, are still object of
debate as well as under current active investigation. The recent
dramatic aging of the population is leading to an increasing
prevalence of neuropsychiatric comorbidities. This is a problem of
great clinical and socio-economical interest, because, when present
in the same subject, depression, parkinsonism-related motor
impairment and cognitive impairment may not only act additively or
synergistically in deteriorating the functional outcome of the
patient, but also lead to their institutionalization. We observed
that one half of institutionalized subjects in two nursing homes of
Central Italy suffer from an associated syndrome dementia /
parkinsonism / depression, that these subjects are significantly
more dependent than subjects hospitalized for the same reasons, and
that their grade of depression or cognitive impairment is
independent of which disease is diagnosed first. Depressed mood,
memory impairment and motor difficulties, however, are often
underestimated in the elderly, being considered as “normal” aspects
of the aging process. The aim of this review is to highlight the
clinical relevance of the associated syndromes of dementia, in a way
that early diagnosis and treatment of these pathologies are
attempted.
Pages 563-575
Gretchen Lorío, Jesús Avila, and Javier Díaz-Nido
Modifications of tau protein during neuronal cell death
Abstract: Accumulation of hyperphosphorylated tau protein and
progressive neuronal loss are among the major hallmarks of certain
neurodegenerative disorders including Alzheimer´s disease. However,
the relationship between tau phosphorylation and neuronal cell death
remains unclear. Here we have analyzed tau modifications during two
forms of neuronal death, apoptosis and necrosis, using primary
cultures of cerebellar granule neurons as a simple model system.
Induction of neuronal apoptosis by inhibition of
phosphatidylinositol 3-kinase results in a rapid increase in the
phosphorylation of tau, which is followed by the dephosphorylation
and cleavage of the protein. In contrast, necrosis triggered by high
salt shock or glutamate treatment leads to a rapid dephosphorylation
and an almost complete proteolysis of tau. These data suggests that
a transient tau hyperphosphorylation occurs at an early stage of
apoptosis, whereas tau is dephosphorylated and cleaved during the
late phase of apoptosis as well as in necrotic neurons.
Pages 577-584
Mst. Shahanara Hossaina, M. Abdul Alim, Kazuya Takeda, Hiroyuki
Kaji, Tomotaka Shinoda and Kenji Uéda
Limited Proteolysis of NACP/alpha-Synuclein
Abstract: The NAC region of NACP/alpha-synuclein is a
secondary component of Alzheimer's disease amyloid. Alpha-Synuclein
is a major component of Lewy bodies, a typical neuropathological
feature of Parkinson's disease. However, the physiological role and
deposition mechanisms of alpha-synuclein are unknown. Structural
analyses of alpha-synuclein should provide a better understanding of
its biochemical characteristics. We investigated the digestion of
alpha-synuclein with alpha-chymotrypsin and cathepsin D, which are
reported to be involved in amyloidogenesis, under various conditions
in vitro. There are many putative cleavage sites for these enzymes
in alpha-synuclein, including in the NAC region. However, most of
the predicted sites remained undigested, and the NAC region was
found to be intact even after extensive digestion. This peculiar
characteristic of alpha-synuclein may be relevant to the abnormal
deposition of this molecule in alpha-synuclein-associated
neurodegenerative diseases.
Pages 585-591
Zhenchao Guo, Chengxuan Qiu, Matti Viitanen, Johan Fastbom, Bengt
Winblad, Laura Fratiglioni
Blood pressure and dementia in persons 75+ years old: 3-year
follow-up results from the Kungsholmen Project
Abstract: A community cohort of 1270 non-demented 75+ years
old persons was followed to evaluate the influence of blood pressure
on incidence of dementia. Two hundred and eighteen dementia cases
were detected during an average of three years of follow-up.
Subjects with baseline systolic pressure >180 mm Hg had an age- and
gender-adjusted relative risk (RR) of 1.6 (95% confidence interval
[CI] = 1.1, 2.5) compared to persons with systolic pressure of
141-160 mm Hg. This association persisted, although not
statistically significant, when education, vascular diseases, and
antihypertensive drug use were entered in the model (RR = 1.4; 95%
CI = 0.9, 2.2). Diastolic pressure and low systolic pressure were
not related to dementia incidence. However, individuals with a
decrease of 5-19 mm Hg and ³20 mm Hg in systolic pressure from
baseline to follow-up had a RR of 1.8 (95% CI = 1.2, 2.6) and 2.5
(95% CI = 1.8, 3.4), respectively. Increased RRs were also found in
subjects with diastolic pressure reduction. In conclusion, our
findings support an association between high systolic pressure and
increased risk of dementia, whereas blood pressure reduction may be
secondary to the dementia process itself.
Pages 593-598
Yuan Luo and Vernon M. Ingram (communicated by Thomas Shea)
Uncoupling of mitochondria activates protein phosphatases and
inactives MBP protein kinases
Abstract: Dephosphorylation of PHF-Tau was observed in
carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone
(FCCP)-treated, but not in oligomycin–treated undifferentiated PC12
cells. FCCP depletes ATP levels by uncoupling oxidative
phosphorylation and increases cytosolic calcium levels, while
oligomycin inhibits the ATP synthase. We also observed inactivation
of several myelin basic protein (MBP) kinases in FCCP-treated PC12
cells, using an in-gel kinase assay. In addition, several
phosphotyrosine proteins were dephosphorylated following
FCCP-treatment. These studies suggest that MBP kinases and tyrosine
phosphatase may be regulated by mitochondrial activity and they may
regulate the phosphorylation state of tau. Since mitochondrial
dysfunction occurs in Alzheimer disease, such changes in protein
phosphorylation may well be relevant to the disease.
Pages 599-600
Letter to the Editor:
Norbert Rösler, Ildiko Wichart, and Kurt A. Jellinger
CSF Aß40 and Aß42: Natural course and clinical usefulness
Pages 601-602
Book Review: Molecular Mechanisms of Neurodegenerative
Diseases. Marie-Françoise Chesselet (Ed), Humana Press Inc., Totowa,
New Jersey, 2001, 410pp. Reviewed by: Zaven S. Khachaturian
Pages 603-604
Book Review: Neuronal Signal Transduction and Alzheimer’s
Disease. O’Neill C and Anderton B (Eds), Portland Press Ltd.,
London, 2001, 221pp. Reviewed by: Mervyn J. Monteiro
Page 605
List of Reviewers
Pages 607-611
Author Index of Volume 3
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