| Volume 4, Number
4, August 2002
Pages 261-267
Thomas B. Shea, James Lyons-Weiler and Eugene Rogers
Homocysteine, folate deprivation and Alzheimer neuropathology
Abstract: Increased levels of homocysteine (HC), arising in
some situations via deficiencies in folate – an essential cofactor
in metabolic regulation of HC – have long been known to contribute
to cardiovascular disorders and stroke. More recently, clinical
studies implicate increased HC and reduced folate with
neurodegenerative conditions including Alzheimer’s disease. It has
remained unclear from clinical studies whether the neurotoxicity of
increased HC and/or reduced folate is derived from direct
detrimental effects on neurons themselves, or is instead derived
indirectly following perturbation of nervous system vasculature.
However, recent reports from several laboratories provide evidence
that HC not only induces direct neurotoxicity, but also potentiates
both amyloid-beta and glutamate neurotoxicity. These latter studies
leave open the possibility that even mild elevations in HC may place
neurons at risk for additional trauma. The potential contribution
of folate deficiency and resultant increases in HC to
neurodegeneration in AD, and therapeutic approaches to alleviate
their impact, is discussed.
Pages 269-281
Philip Grant and Harish C. Pant (Communicated by Thomas Shea)
Abnormal topographic regulation of kinase activity in Alzheimer's
disease brains
Abstract: At autopsy, a most distinctive pathology seen in
Alzheimer's disease (AD) brains is numerous abnormal neurons filled
with neurofibrillary tangles (NFTs) containing stable complexes of
hyperphosphorylated tau (PHF), neurofilaments and various kinases,
among other proteins. Though these neuronal aggregates have been
actively studied, their nature and origin are still poorly
understood. Our studies of regulation of phosphorylation in neurons
of the squid giant fiber system, using P13suc1 affinity
chromatography, suggest that neuronal phosphorylation of
cytoskeletal proteins is compartmentalized into active axonal and
inactive cell body-specific multimeric complexes of kinases,
substrates and phosphatases. To determine whether such
compartment-specific phosphorylation complexes are present in human
brains, we separated gray matter (enriched in cell bodies) and white
matter (enriched in axons) from normal and AD brains and studied the
total kinase activities in lysates, pellets and P13suc1 complexes.
In addition, Western blot analysis was used to characterize the
proteins associated with P13suc1 multimeric complexes extracted from
gray and white matter. We tested the hypothesis that phosphorylation
complexes were abnormally compartmentalized in AD neurons with the
more active complexes shifted to cell bodies rather than axons. We
found that in contrast to normal neurons, AD neurons exhibited(1)
lower kinase activities, (2) a shift of kinase activities from
soluble to insoluble complexes in cell bodies (3) higher kinase
activities in cell bodies compared to axons, and (4) profiles of
P13suc1 -associated kinases and cytoskeletal proteins in AD gray and
white matter similar to normal P13 patterns, except for higher
expression of phosphorylated NF-H and PHF-tau in gray matter of AD
brains. In comparison to normal brains, the data suggest that
topological organization of phosphorylation complexes in AD brains
was deregulated.
Pages 283-289
Patrick Brunelle and Arvi Rauk (Communicated by D. Allan
Butterfield)
The Radical Model of Alzheimer’s Disease: specific recognition of
Gly29 and Gly33 by Met35 in a ß-sheet model of Aß: an ONIOM study
Abstract: The Radical Model of Alzheimer’s Disease (AD) is
presented in some detail. The model provides a unified picture for
the role of the amyloid beta peptide (Aß), Met35, copper ions,
oxygen, beta sheet secondary structure, and the generation of
hydrogen peroxide, in mediating oxidative stress in AD. It predicts
a role for glycyl radicals as long-lived species which can transport
the damage into cell membranes and initiate lipid peroxidation.
Previous work has established the thermodynamic and kinetic
viability of most of the steps. In the present work, QM/MM and
Amber calculations reveal that self assembly of antiparallel ß-sheet
which brings Met35 into the required close proximity to a glycine
residue is more likely if the residue is Gly29 or Gly33, than any of
the other four glycine residues of Aß.
Pages 291-301
Ratan V. Bhat, Sergey Leonov, Johan Luthman, Clay W Scott, Chi-Ming
Lee
Interactions between GSK3ß and caspase signalling pathways during
NFG deprivation induced cell death
Abstract: Withdrawal of NGF (NGF-W) in PC12 cells leads to
caspase and GSK3ß activation which results in cell death. Our recent
findings suggest that inhibition of GSK3ß promotes PC12 cell
survival after NGF-W. To determine whether these pathways interact
from a signalling perspective, we compared the effects of BAF (a
general caspase inhibitor), Li+ (a GSK3ß inhibitor) and
insulin on NGF-W induced PC12 cell death. Maximal increase in DNA
fragmentation was observed 3 h after NGF-W and was inhibited by BAF
(7.5 uM), Li+ (IC50=2 mM) and insulin (IC50=100
nM). BAF inhibited caspase-3 activity and delayed cell death up to
6h after NGF-W indicating that caspase inhibition is sufficient to
prevent apoptosis. BAF had no major effect on GSK3ß active site
phosphorylation or activity suggesting the caspase pathway does not
regulate GSK3ß activity. Conversely, Li+ inhibited
caspase activity by only 20% but promoted cell survival for 24 h
after NGF-W. Overexpression of dominant negative mutants of GSK3ß
also inhibited apoptosis, but had only a minor effect on caspase
activity after NGF-W. Taken together, these results suggest that
GSK3ß is upstream of caspase signalling, and exerts a small effect
on the caspase pathway.
Pages 303-308
Rishi D.S. Nandoe, Philip Scheltens, Piet Eikelenboom
Head trauma and Alzheimer’s disease. A case report and review of
the literature
Abstract: The authors describe a case of a 55 year old woman
who was diagnosed with Alzheimer’s disease 1.5 years after a car
accident in which she experienced a mild concussion. Extensive
history taking disclosed no cognitive changes prior to the car
accident. The case is discussed in view of the inflammation
hypothesis regarding Alzheimer’s disease and the role of the
apolipoprotein E4 genotype of the patient.
Pages 309-315
Qiao-Xin Li , Bruce C.V. Campbell, Catriona A. McLean, Domimic
Thyagarajan, Wei-Ping Gai, Robert M. Kapsa, Konrad Beyreuther,
Colin.L. Masters, Janetta G. Culvenor (Communicated by Ralph
Martins)
Platelet alpha- and gamma-synucleins in Parkinson's disease and
normal control subjects
Abstract: alpha-Synuclein (alphaSN) has been implicated in
Parkinson's Disease (PD) and alphaSN is a major component of Lewy
bodies. This study explored platelets as a model system for study of
alphaSN metabolism and platelet alphaSN as a diagnostic marker for
PD. We used Western blot analysis to characterize and compare
platelet and brain alpha-, ß- and gammaSN; and to quantitate alphaSN
levels in platelets from PD and age-matched controls. We found that
platelets contain full-length alphaSN and 6 and 12 kDa fragments,
and gammaSN-like protein. alphaSN and gammaSN were not secreted by
thrombin-activated platelets. Furthermore, we also found that the
alphaSN and gammaSN levels in sporadic PD patients and age-matched
normal controls were not significantly different. This indicates
that platelet alphaSN or gammaSN is not a suitable peripheral
diagnostic marker for PD. Platelets may be used for study of alphaSN
and gammaSN metabolism, and may give some broad insight into the
normal functions of alphaSN and gammaSN.
Pages 317-325
Marwan N. Sabbagh, Ronald J. Lukas, D. Larry Sparks, Richard T. Reid
(Communicated by James Geddes)
The Nicotinic Acetylcholine Receptor, Smoking, and Alzheimer’s
Disease
Abstract: Cholinergic dysfunction is one of the cornerstones
of Alzheimer’s disease (AD) pathology. Reviewed here is evidence
evaluating relationships between smoking, nicotine exposure,
nicotinic cholinergic signaling, and AD. Epidemiological studies
initially indicating a lower incidence of AD in smokers now suggest
conflicting results. Clinicopathological findings also are mixed as
to how smoking behavior affects manifestation of AD markers. Studies
that show nicotine-induced increases in nicotinic acetylcholine
receptors (nAChR) and protection against age-related nAChR decline
contrast, perhaps in a functionally relevant way, to losses of nAChR
in AD. Although epidemiological, clinicopathological, and functional
studies in humans do not present a cohesive picture, much in vitro
data suggests neuroprotective properties of nicotine when used in
models of neurodegenerative disorders. Studies of nicotine and
nicotinic agonist effects on cognitive function in the non-demented
and in AD are not compelling. More work is needed to ascertain
whether acute or repetitive activation of nAChR with acute or
intermittent exposure to nicotine or the persistent inactivation of
nAChR with chronic nicotine exposure is a therapeutic objective
and/or explains any pro-cognitive effects of those drugs. Other
studies show complex interactions between nAChR, nicotinic agonists,
and agents implicated in AD etiology. Thus, while controversies
still exist, ongoing research is illuminating how nicotinic receptor
changes and functions may be relevant to clinical, pathological and
neurochemical changes that occur in AD.
Pages 327-328
Kurt A. Jellinger, Klaus Seppi, and Gregor K. Wenning
Letter to the Editor: Lewy bodies in patients presenting
clinically with Alzheimer disease
Pages 329-330
Hernando Rafael, Eudocio Fernández, Víctor Ayulo
Letter to the Editor regarding Guo et al., J Alzheimer’s Disease
3:585-591, 2001
Page 331
Chengxuan Qiu, Laura Fratiglioni
Response to Letter to the Editor regarding Guo et al., J
Alzheimer’s Disease 3:585-591, 2001
Pages 333-334
Book Review: Close to Me, But Far Away by Burton M. Wheeler.
University of Missouri Press, 2001, 176pp. Reviewed by Carlos Garcia
Pages 335-336
Book Review: Neuroglia in the Aging Brain, Jean de Vellis,
Ed. Humana Press: Totowa, NJ, 2001, 546pp. Reviewed by Caleb E Finch
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