| Volume 2, Number
2, June 2000
Pages 69-78
Anne C. Andorn and Rajesh N. Kalaria
Factors affecting pro- and anti-oxidant properties of fragments
of the ß-protein precursor (ßPP): implication for Alzheimer's
disease
Abstract: Oxidative stress may have a key pathogenetic role
in neurodegenerative diseases including Alzheimer's disease (AD).
While there is evidence that some amyloid-ß (Aß) peptides can
initiate oxidative stress at micromolar doses, there is also some
evidence that oxidative stress increases the concentration of the
ß-protein precursor (ßPP) and the potential for increased formation
of the Aß peptides. The following studies were performed to test
the hypothesis that fragments of ßPP could be antioxidants and hence
that oxidative stress might be an early event in AD. We found that
several fragments of ßPP, including the Aß peptides, inhibit
ascorbate-stimulated lipid peroxidation (ASLP) in membrane fragment
preparations of postmortem human brain. In contrast, other
fragments of ßPP enhance ASLP. These data indicate that ßPP or
fragments of ßPP could play a key role in the redox status of cells
and that alterations in ßPP processing could have profound effects
on the cellular response to oxidative stress.
Commentary on the Andorn and
Kalaria manuscript:
Pages 79-82
Miguel Pappolla
Oxidative stress and the amyloid conundrum. What is the
connection?
Pages 83-84
Ashley I. Bush, Craig S. Atwood, Lee E. Goldstein, Xudong Huang,
Jack Rogers
Could Aß and ßPP be antioxidants?
Pages 85-93
William K. Summers
Tacrine (THA, COGNEX®)
Summary: AD affects numerous neurotransmitter systems. The
most predominant neurotransmitter involved is a reduction in the
cholinergic system. Anatomically, the cholinergic neurons in the
septal-diagonal band of Broca-nucleus basalis system is most
effected in AD. Dysfunction in the cholinergic system is closely
linked to memory capacity deficits. It is specifically this system
that is enhanced by cholinesterase inhibitors such as tacrine.
Tacrine has been studied for sixty years. In Australia, Adrian
Albert was attempting to find a safe intravenous antiseptic to
assist in the Second World War. His efforts were interrupted by the
British discovery of Penicillin. He remained intrigued by tacrine
because of its unique properties of reversing anesthetic induced
sleep. Although several of the more than ninety monoaminoacridines
Dr. Albert synthesized had CNS arousal effects, tacrine stood out.
Later work demonstrated that this broad spectrum arousal of the
central nervous system was due to the reversible
acetylcholinesterase inhibition. Tacrine is a planar three-ring
acridine with minimal substitution of an amino group in the five
position. Because of the flat configuration like a frisbee and the
high pKa of 10, tacrine has the capacity to slice through cell
membranes almost as easily as ethyl alcohol. This property made
tacrine unique. In the 1950's tacrine was used experimentally to
reverse cholinergic coma in animals. Gershon et al. used tacrine in
the 1960's to reverse the effects of phencyclidine like drugs. In
1980, Summers et al. demonstrated that intravenous tacrine could
practically be used to treat some overdose comas. In 1981,
intravenous tacrine was used in AD patients to support the
cholinergic hypothesis. In nine of twelve subjects with putative AD,
intravenous tacrine demonstrated a beneficial short term effect.
Benefit was best seen by separating the subjects into the stage of
illness. In the early stages, instruments such as name memorization
lists were able to measure drug effect. In the late stages of
dementia, different instruments had to be used. The important point
is that tacrine did give a beneficial response in all stages of AD,
but that different instruments had to be used at different stages.
This subtle point has been missed in subsequent literature.
Pages 95-96
Steven C. Samuels, Kenneth Davis
Commentary on the Summers manuscript
Pages 97-108
Ming Chen and Hugo L. Fernandez
Revisiting Alzheimer's disease from a new perspective: can “risk
factors” play a key role?
Abstract: Alzheimer's disease (AD) has been intensively
studied for decades, but why has its common “pathological cause"
remained so enigmatic? Our studies have suggested that plaques and
tangles occur "spontaneously" during aging as a result of a
"natural" decline of energy metabolism and Ca2+ signaling, but not
necessarily due to conventional "pathogens". This view would lead
to an unexpected outcome, that is, natural aging plays a more
important role in neurodegeneration than it is currently
recognized. Does this model overly simplify the disease origin? We
know that AD-type neurodegeneration typically occurs at the end
stages of life when not only do plaques and tangles appear, but also
many other bodily changes (bone loss and skin wrinkling, etc).
Neurodegeneration differs from the latter changes mainly by "social"
consequences, not by "physiological" origin. If neurodegeneration
is a natural event, then why do only some people, but not others,
develop AD? Obviously, additional factors are required for
neurodegeneration to develop into AD. By comparing current models
and ruling out other possibilities, we think that several known
“risk factors” most likely play a critical role in the late-onset
sporadic AD. These risk factors can exert their effects either by
providing the conditions for ailing neurons to die (extended
longevity and sedentary lifestyle), or by enhancing the individual's
"vulnerability" to natural neurodegeneration (low synapse reserve).
By this view, the late-onset sporadic AD would be similar to many
other age-related conditions where perhaps no any single “pathogen”
can be held exclusively responsible for most cases, but rather many
risk factors are important to allow the initial defect to develop
into clinical symptoms. Accordingly, these factors should be the
primary targets for AD prevention. Yet, some other AD cases,
especially the “early-onset” ones, may be complicated by the
concomitant involvement of other diseases in the brain.
Commentary on the Chen and
Fernandez manuscript:
Pages 109-112
Mark P. Mattson
Risk Factors and Mechanisms of Alzheimer’s Disease
Pathogenesis: Obviously and Obviously Not
Pages 113-114
J. L. Price, D. Phil, E. H. Rubin, J. C. Morris
Revisiting Alzheimer’s disease from a new prospective: can
“risk factors” play a key role
Pages 115-116
Zaven S. Khachaturian
Aging: a cause or a risk for AD?
Page 117
Hossein Ghanbari
Risk factors versus Alzheimer’s disease or symptoms
associated with Alzheimer’s disease
Pages 119-121
Ming Chen and Hugo L. Fernandez
Reply: How important are risk factors in Alzheimer’s disease?
Pages 123-131
Servet M. Yatin, Sridhar Varadarajan, and D. Allan Butterfield
(communicated by Mark Kindy)
Vitamin E prevents Alzheimer’s amyloid ß-peptide (1-42)-induced
neuronal protein oxidation and reactive oxygen species production
Abstract: Amyloid ß-peptide (Aß) is a 42-43 amino acid
peptide known to accumulate in Alzheimer’s disease (AD) brain. We
previously reported that the neurotoxicity caused by Aß is a result
of its associated free radicals, which can play an important role in
generating oxidative stress. Aß(25-35)-associated oxidative
stress-induced neuronal death in vitro is well established by
many laboratories, including ours. However, the oxidative
stress-induced by the full-length [Aß(1-42)] peptide is not well
investigated. The protective effect of antioxidant vitamin E in
full-length peptide-induced oxidative stress also has not been
reported. Here, we report that the increased protein oxidation,
reactive oxygen species (ROS) formation, and neurotoxicity induced
by Aß(1-42) in primary rat embryonic hippocampal neuronal culture
are prevented by the free radical scavenger and antioxidant vitamin
E. To test the hypothesis that vitamin E’s protective effect may be
due to inhibition of fibrils formation, electron microscopy studies
were undertaken. Vitamin E does not inhibit Aß(1-42) fibril
formation, suggesting that the neuroprotection afforded by this
molecule stems from other processes, most probably through the
scavenging of Aß-associated free radicals. These results may have
implications on the treatment of Alzheimer’s disease.
Commentary on the Yatin et al.
manuscript:
Pages 133-135
Kimberly L. Clapp-Lilly and Lawrence K. Duffy
Amyloid Fibril Toxicity Still Unresolved
Pages 137-149
Barbara J. Blanchard, Anne E. Hiniker, Connie C. Lu, Yelena
Margolin, Amy S. Yu, Vernon M. Ingram (communicated by Thomas
Shea)
Elimination of ß–Amyloid Neurotoxicity
Abstract: Aggregation of the Alzheimer ß-amyloid peptide
Aß1-42 forms neurotoxic fibrils. In contact with human neurons the
fibrils cause rapid influx of external calcium through
AMPA/kainate-channels. If this molecular mechanism reflects in vivo
events, it could explain the pathogenesis of Alzheimer's disease;
activation of AMPA/kainate channels is therefore a likely target for
therapeutic intervention. Here we show that short antagonistic
“decoy peptides”, made of D-amino acids, eliminate this “calcium
effect” of Aß1-42. Since chronically elevated calcium levels in the
disease trigger activation of pathways that lead to neuron
dysfunction and cell death, our decoy peptides are obvious
candidates for drug development.
Pages 151-191
Proceedings from the 6th Conference on Neurodegenerative Disorders:
Common Molecular Mechanisms
April 8-14, 2000, Trinidad and Tobago, West Indies
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