Journal of Alzheimer's disease
David Small
Alzheimer's Disease, from now on the contents and abstracts from the latest=
=20
issue of Journal of Alzheimer's Disease will be listed on the Amyloid=20
Newsgroup.
The contents and abstracts from Volume 2, number 2 are shown=20
below. Abstracts of other issues can be obtained at the Journal website=20
located at http://www.j-alz.com.
Anne C. Andorn and Rajesh N. Kalaria
Factors affecting pro- and anti-oxidant properties of fragments of the=20
=DF-protein precursor (=DFPP): implication for Alzheimer's disease
Abstract: Oxidative stress may have a key pathogenetic role in=20
neurodegenerative diseases including Alzheimer's disease (AD). While there=
=20
is evidence that some
amyloid-=DF (A=DF) peptides can initiate oxidative stress at micromolar=
doses,=20
there is also some evidence that oxidative stress increases the=20
concentration of the
=DF-protein precursor (=DFPP) and the potential for increased formation of=
the=20
A=DF peptides. The following studies were performed to test the hypothesis=
that
fragments of =DFPP could be antioxidants and hence that oxidative stress=20
might be an early event in AD. We found that several fragments of =DFPP,=20
including the A=DF
peptides, inhibit ascorbate-stimulated lipid peroxidation (ASLP) in=20
membrane fragment preparations of postmortem human brain. In contrast,=20
other fragments of
=DFPP enhance ASLP. These data indicate that =DFPP or fragments of =DFPP=
could=20
play a key role in the redox status of cells and that alterations in =DFPP=
=20
processing
could have profound effects on the cellular response to oxidative stress.
Commentary on the Andorn and Kalaria manuscript:
Miguel Pappolla
Oxidative stress and the amyloid conundrum. What is the connection?
Ashley I. Bush, Craig S. Atwood, Lee E. Goldstein, Xudong Huang, Jack=
=20
Rogers
Could A=DF and =DFPP be antioxidants?
William K. Summers
Tacrine (THA, COGNEX=AE)
Summary: AD affects numerous neurotransmitter systems. The most=20
predominant neurotransmitter involved is a reduction in the cholinergic=20
system. Anatomically,
the cholinergic neurons in the septal-diagonal band of Broca-nucleus=20
basalis system is most effected in AD. Dysfunction in the cholinergic=20
system is closely linked
to memory capacity deficits. It is specifically this system that is=20
enhanced by cholinesterase inhibitors such as tacrine. Tacrine has been=20
studied for sixty years. In
Australia, Adrian Albert was attempting to find a safe intravenous=20
antiseptic to assist in the Second World War. His efforts were interrupted=
=20
by the British
discovery of Penicillin. He remained intrigued by tacrine because of its=20
unique properties of reversing anesthetic induced sleep. Although several=20
of the more than
ninety monoaminoacridines Dr. Albert synthesized had CNS arousal effects,=20
tacrine stood out. Later work demonstrated that this broad spectrum arousal=
=20
of the
central nervous system was due to the reversible acetylcholinesterase=20
inhibition. Tacrine is a planar three-ring acridine with minimal=20
substitution of an amino group
in the five position. Because of the flat configuration like a frisbee and=
=20
the high pKa of 10, tacrine has the capacity to slice through cell=20
membranes almost as easily
as ethyl alcohol. This property made tacrine unique. In the 1950's tacrine=
=20
was used experimentally to reverse cholinergic coma in animals. Gershon et=
=20
al. used
tacrine in the 1960's to reverse the effects of phencyclidine like drugs.=20
In 1980, Summers et al. demonstrated that intravenous tacrine could=20
practically be used to
treat some overdose comas. In 1981, intravenous tacrine was used in AD=20
patients to support the cholinergic hypothesis. In nine of twelve subjects=
=20
with putative
AD, intravenous tacrine demonstrated a beneficial short term=20
effect. Benefit was best seen by separating the subjects into the stage of=
=20
illness. In the early stages,
instruments such as name memorization lists were able to measure drug=20
effect. In the late stages of dementia, different instruments had to be=20
used. The important
point is that tacrine did give a beneficial response in all stages of AD,=20
but that different instruments had to be used at different stages. This=20
subtle point has been
missed in subsequent literature.
Steven C. Samuels, Kenneth Davis
Commentary on the Summers manuscript
Ming Chen and Hugo L. Fernandez
Revisiting Alzheimer's disease from a new perspective: can =93risk factors=
=94=20
play a key role?
Abstract: Alzheimer's disease (AD) has been intensively studied for=20
decades, but why has its common =93pathological cause" remained so=20
enigmatic? Our studies
have suggested that plaques and tangles occur "spontaneously" during aging=
=20
as a result of a "natural" decline of energy metabolism and Ca2+ signaling,=
=20
but not
necessarily due to conventional "pathogens". This view would lead to an=20
unexpected outcome, that is, natural aging plays a more important role in
neurodegeneration than it is currently recognized. Does this model overly=
=20
simplify the disease origin? We know that AD-type neurodegeneration=20
typically occurs
at the end stages of life when not only do plaques and tangles appear, but=
=20
also many other bodily changes (bone loss and skin wrinkling,=20
etc). Neurodegeneration
differs from the latter changes mainly by "social" consequences, not by=20
"physiological" origin. If neurodegeneration is a natural event, then why=
=20
do only some
people, but not others, develop AD? Obviously, additional factors are=20
required for neurodegeneration to develop into AD. By comparing current=20
models and
ruling out other possibilities, we think that several known =93risk factors=
=94=20
most likely play a critical role in the late-onset sporadic AD. These risk=
=20
factors can exert
their effects either by providing the conditions for ailing neurons to die=
=20
(extended longevity and sedentary lifestyle), or by enhancing the=20
individual's "vulnerability"
to natural neurodegeneration (low synapse reserve). By this view, the=20
late-onset sporadic AD would be similar to many other age-related=20
conditions where
perhaps no any single =93pathogen=94 can be held exclusively responsible for=
=20
most cases, but rather many risk factors are important to allow the initial=
=20
defect to
develop into clinical symptoms. Accordingly, these factors should be the=20
primary targets for AD prevention. Yet, some other AD cases, especially the
=93early-onset=94 ones, may be complicated by the concomitant involvement of=
=20
other diseases in the brain.
Commentary on the Chen and Fernandez manuscript:
Mark P. Mattson
Risk Factors and Mechanisms of Alzheimer=92s Disease Pathogenesis:=20
Obviously and Obviously Not
J. L. Price, D. Phil, E. H. Rubin, J. C. Morris
Revisiting Alzheimer=92s disease from a new prospective: can =93risk=20
factors=94 play a key role
Zaven S. Khachaturian
Aging: a cause or a risk for AD?
Hossein Ghanbari
Risk factors versus Alzheimer=92s disease or symptoms associated with=
=20
Alzheimer=92s disease
Ming Chen and Hugo L. Fernandez
Reply: How important are risk factors in Alzheimer=92s disease?
Servet M. Yatin, Sridhar Varadarajan, and D. Allan Butterfield=20
(communicated by Mark Kindy)
Vitamin E prevents Alzheimer=92s amyloid =DF-peptide (1-42)-induced=
neuronal=20
protein oxidation and reactive oxygen species production
Abstract: Amyloid =DF-peptide (A=DF) is a 42-43 amino acid peptide known to=
=20
accumulate in Alzheimer=92s disease (AD) brain. We previously reported that=
the
neurotoxicity caused by A=DF is a result of its associated free radicals,=20
which can play an important role in generating oxidative stress.=20
A=DF(25-35)-associated
oxidative stress-induced neuronal death in vitro is well established by=20
many laboratories, including ours. However, the oxidative stress-induced by=
=20
the full-length
[A=DF(1-42)] peptide is not well investigated. The protective effect of=20
antioxidant vitamin E in full-length peptide-induced oxidative stress also=
=20
has not been
reported. Here, we report that the increased protein oxidation, reactive=20
oxygen species (ROS) formation, and neurotoxicity induced by A=DF(1-42) in=
=20
primary rat
embryonic hippocampal neuronal culture are prevented by the free radical=20
scavenger and antioxidant vitamin E. To test the hypothesis that vitamin=20
E=92s protective
effect may be due to inhibition of fibrils formation, electron microscopy=20
studies were undertaken. Vitamin E does not inhibit A=DF(1-42) fibril=20
formation, suggesting
that the neuroprotection afforded by this molecule stems from other=20
processes, most probably through the scavenging of A=DF-associated free=20
radicals. These
results may have implications on the treatment of Alzheimer=92s disease.
Commentary on the Yatin et al. manuscript:
Kimberly L. Clapp-Lilly and Lawrence K. Duffy
Amyloid Fibril Toxicity Still Unresolved
Barbara J. Blanchard, Anne E. Hiniker, Connie C. Lu, Yelena Margolin, Amy=20
S. Yu, Vernon M. Ingram (communicated by Thomas Shea)
Elimination of =DF=ADAmyloid Neurotoxicity
Abstract: Aggregation of the Alzheimer =DF-amyloid peptide A=DF1-42 forms=20
neurotoxic fibrils. In contact with human neurons the fibrils cause rapid=20
influx of external
calcium through AMPA/kainate-channels. If this molecular mechanism reflects=
=20
in vivo events, it could explain the pathogenesis of Alzheimer's disease;=20
activation of
AMPA/kainate channels is therefore a likely target for therapeutic=20
intervention. Here we show that short antagonistic =93decoy peptides=94,=
made=20
of D-amino acids,
eliminate this =93calcium effect=94 of A=DF1-42. Since chronically elevated=
=20
calcium levels in the disease trigger activation of pathways that lead to=20
neuron dysfunction and
cell death, our decoy peptides are obvious candidates for drug development.
Proceedings from the 6th Conference on Neurodegenerative Disorders: Common=
=20
Molecular Mechanisms
April 8-14, 2000, Trinidad and Tobago, West Indies=20
David Small
The contents and abstracts from Volume 2, number 2 are shown
below. Abstracts of other issues can be obtained at the Journal website
located at http://www.j-alz.com.
Anne C. Andorn and Rajesh N. Kalaria
Factors affecting pro- and anti-oxidant properties of fragments of the
beta-protein precursor (betaPP): 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 someamyloid-beta (Abeta) peptides can initiate oxidative
stress at micromolar
doses,there is also some evidence that oxidative stress increases the
beta-protein precursor (betaPP) and the potential for increased formation
of the
Abeta peptides. The following studies were performed to test the hypothesis
thatfragments of betaPP could be antioxidants and hence that oxidative stress
might be an early event in AD. We found that several fragments of betaPP,
including the Abeta peptides, inhibit ascorbate-stimulated lipid
peroxidation (ASLP) in
membrane fragment preparations of postmortem human brain. In contrast,
other fragments of betaPP enhance ASLP. These data indicate that betaPP or
fragments of betaPP
could play a key role in the redox status of cells and that alterations
in betaPP
processing could have profound effects on the cellular response to
oxidative stress.
Commentary on the Andorn and Kalaria manuscript:
Miguel Pappolla
Oxidative stress and the amyloid conundrum. What is the connection?
Ashley I. Bush, Craig S. Atwood, Lee E. Goldstein, Xudong Huang,
JackRogers
Could Abeta and betaPP be antioxidants?
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.
Steven C. Samuels, Kenneth Davis
Commentary on the Summers manuscript
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:
Mark P. Mattson
Risk Factors and Mechanisms of Alzheimer's Disease Pathogenesis:
Obviously and Obviously Not
J. L. Price, D. Phil, E. H. Rubin, J. C. Morris
Revisiting Alzheimers disease from a new prospective: can risk
factors play a key role
Zaven S. Khachaturian
Aging: a cause or a risk for AD?
Hossein Ghanbari
Risk factors versus Alzheimers disease or symptoms associated with
Alzheimers disease
Ming Chen and Hugo L. Fernandez
Reply: How important are risk factors in Alzheimers disease?
Servet M. Yatin, Sridhar Varadarajan, and D. Allan Butterfield
(communicated by Mark Kindy)
Vitamin E prevents Alzheimers amyloid beta-peptide (1-42)-induced
neuronal protein oxidation and reactive oxygen species production
Abstract: Amyloid beta-peptide (Abeta) is a 42-43 amino acid peptide known to
accumulate in Alzheimers disease (AD) brain. We previously reported that
the neurotoxicity caused by Abeta is a result of its associated free
radicals,
which can play an important role in generating oxidative stress.
Abeta(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 [Abeta(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 Abeta(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
Es protective effect may be due to inhibition of fibrils formation,
electron microscopy
studies were undertaken. Vitamin E does not inhibit Abeta(1-42) fibril
formation, suggesting that the neuroprotection afforded by this molecule
stems from other
processes, most probably through the scavenging of Abeta-associated free
radicals. These results may have implications on the treatment of
Alzheimers disease.
Commentary on the Yatin et al. manuscript:
Kimberly L. Clapp-Lilly and Lawrence K. Duffy
Amyloid Fibril Toxicity Still Unresolved
Barbara J. Blanchard, Anne E. Hiniker, Connie C. Lu, Yelena Margolin, Amy
S. Yu, Vernon M. Ingram (communicated by Thomas Shea)
Elimination of AD Amyloid Neurotoxicity
Abstract: Aggregation of the Alzheimer beta-amyloid peptide Abeta1-42 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 Abeta1-42. 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.
Proceedings from the 6th Conference on Neurodegenerative Disorders: Common