| Volume 3, Number
4, August 2001
Pages 355-366
T. W. Stone, W.M.H. Behan, P.A. Jones , L. G. Darlington and R. A.
Smith
The role of kynurenines in the production of neuronal death, and
the neuroprotective effect of purines.
Abstract: The kynurenine metabolic pathway from tryptophan
accounts for a large proportion of the metabolism of this amino acid
in the brain. Although a major route for the generation of the
essential co-factor nicotinamide adenine dinucleotide (NAD), two
components of the pathway have marked effects on neurons. Quinolinic
acid is an agonist at N-methyl-D-aspartate (NMDA)-sensitive
glutamate receptors, while kynurenic acid is an antagonist and,
thus, a potential neuroprotectant. The levels of quinolinic acid are
known to increase substantially following cerebral insults or
infection, and has been most clearly implicated in the AIDS-dementia
complex. The actions of quinolinic acid and NMDA show subtle
differences, however, which suggest other factors contributing to
cell damage. In this article we review the evidence that free
radicals may be involved in the neurotoxic effects of quinolinic
acid and consider the possibility that quinolinic acid might be
involved in Alzheimer's disease. Finally, adenosine receptor ligands
can modulate neuronal damage, supporting the view that they may
represent suitable targets for the development of novel
neuroprotectant drugs for the treatment of Alzheimer's and other
neurodegenerative diseases.
Pages 367-375
Larry F. Hughes, Robert G. Struble, and Carla L. Shaffer
Olfaction in elderly and Alzheimer patients: differing feedback
conditions
Abstract: Objective: To determine the capability of AD
patients and age-matched controls to discriminate and recognize
odorants equilibrated for strength and familiarity, and to determine
if immediate corrective-feedback can improve performance in either
task.
Major Results: No significant differences between elderly controls
(EC) and AD patients were apparent for the discrimination task
regardless of feedback condition. The EC group outperformed the AD
group on the recognition task. Feedback enhanced EC group
performance but failed to benefit the AD group.
Conclusions: Early in the disease process, AD subjects have a
deficit in processing olfactory cues at levels beyond that necessary
for discrimination. This deficit is specifically related to the
olfactory system and is in addition to any general cognitive
deficits they may have. Feedback is ineffective for AD subjects but
can greatly enhance the performance of the intact elderly on tasks
requiring the verbal mediation of olfactory cues.
Pages 377-385
Srikanth Ranganathan, Susan Scudiere, and Robert Bowser
Hyperphosphorylation of the retinoblastoma gene product and
altered subcellular distribution of E2F-1 during Alzheimer’s disease
and amyotrophic lateral sclerosis
Abstract: The molecular mechanisms that regulate neuronal
cell death in neurodegenerative diseases remain unclear. During
neurologic diseases numerous neuronal and glial intracellular
signaling pathways are activated by changes within the extracellular
environment, which culminate in alterations of nuclear proteins and
gene expression. Among the proteins activated or expressed during
neurodegenerative diseases include proteins that function during the
cell cycle. Early events in cell cycle activation include
transition from the G1 to S phase of the cell cycle, which is
regulated by the activity of proteins from the retinoblastoma (pRb)
and E2F gene families of transcriptional regulators.
Hyperphosphorylation of pRb induces the activation of E2F proteins
at the G1-to-S cell cycle transition. Using brain and spinal cord
tissues from non-demented control, Alzheimer’s disease (AD) and
amyotrophic lateral sclerosis (ALS) patients, we identified
increased levels of hyperphosphorylated pRb in AD and ALS patients.
In addition, we observed altered subcellular distribution of E2F-1
during AD and ALS. Our results suggest that activation and
re-distribution of early cell cycle transcriptional regulators
occurs in both AD and ALS.
Pages 387-391
Othman Ghribi, David A. DeWitt, Michael S. Forbes, Ayala Arad, Mary
M. Herman and John Savory
Cyclosporin A inhibits Al-induced cytochrome c release from
mitochondria in aged rabbits.
Abstract: Neurodegenerative diseases including Alzheimer’s
disease are characterized by a progressive and selective neuronal
loss via an apoptosis mechanism, and there is a growing body of
evidence which supports a central role of mitochondria in this
apoptotic cell death. Release of cytochrome c from the mitochondria
to the cytosol is considered a critical step in apoptosis. Here we
report that aluminum maltolate induces cytochrome c translocation
into the cytosol as early as 3 hours in aged but not in young rabbit
hippocampus. Pretreatment with cyclosporin A, an inhibitor of the
mitochondria permeability transition pore (MTP), blocks cytochrome c
release. Therefore, it appears that aluminum maltolate-induced
cytochrome c release results from opening of the MTP. This effect
implicates aging as a prerequisite factor, since the MTP does not
open in young animals. Mitochondrial injury thus may represent a
primary initiator of neurodegeneration.
Pages 393-396
David J. Figueroa, Xiao-Ping Shi, Stephen J. Gardell, and
Christopher P. Austin (communicated by John Q. Trojanowski)
AßPP secretases are co-expressed with AßPP in the pancreatic
islets
Abstract: Amyloid ß protein precursor is cleaved by ß- and
gamma-secretases to produce Aß peptides which deposit in amyloid
plaques in Alzheimer’s disease (AD) brain. A recently identified
beta-site cleaving enzyme (BACE) appears to fulfill the requirements
for ß-secretase, and presenilin-1 (PS1) appears to constitute the
catalytic component of gamma-secretase. Each protein has a close
homologue (BACE2 and PS2, respectively), whose roles in AßPP
cleavage remain uncertain. All four of these genes have been
reported to be expressed in the human pancreas, but the cell types
expressing these genes remains unknown. We demonstrate here the
cell-specific expression of AßPP, BACE, BACE2, PS1, and PS2 in the
human pancreas. The insulin-producing ß cells were found to express
AßPP, BACE and PS2 at high levels, and PS1 at a lower level. The
other islet cell types expressed none of these five genes. By
contrast, the exocrine ductal cells of the pancreas expressed AßPP
and BACE2 selectively. These results suggest that secretase
inhibitors under development for the treatment of AD, particularly
those that target BACE, may have potential for adverse effects on
pancreatic ß cell function, and therefore glycemic control.
Commentary on the Figueroa et al.
manuscript:
Pages 397-399
Ralph Martins
Amyloid ß Precursor Protein metabolism as a modulator of
Islet ß-Cell Function
Pages 401-407
Yuan Luo (communicated by Thomas Shea)
Ginkgo biloba neuroprotection: therapeutic implications in
Alzheimer’s disease
Abstract: An extract of Ginkgo biloba leaves, EGb761, is
becoming one of the most popular dietary supplements in the United
States to enhance memory. In Europe it is a commonly prescribed drug
for treatment of age-related deterioration, including degenerative
dementias of the Alzheimer type (AD). Substantial experimental
evidence indicates that EGb761 has neuroprotective potency under
conditions such as ischemia, seizures and peripheral nerve damage.
However, the mechanisms of such neuroprotective effects remain
unknown, partially because of the complex chemical composition of
EGb761 and the resulting so-called “polyvalent” action. This review
focuses on cellular and molecular approaches towards understanding
the polyvalent action of EGb761 neuroprotective effect. Two
potential mechanisms of action, reducing oxidative damage and
stimulating cell survival machinery, are discussed. Better
understanding of the neuroprotective mechanisms of EGb761 will
provide impetus for possible combination therapies and for the
design of rational, “mechanism-based” strategies that target
age-related neurodegeneration and Alzheimer’s disease.
Pages 409-415
Carlos Velez-Pardo, Sergio Tobon Arroyave, Francisco Lopera,
Alexandra Duque Castaño and Marlene Jimenez Del Rio
Ultrastructure evidence of necrotic neural cell death in Familial
Alzheimer’s disease brains bearing presenilin-1 E280A mutation
Abstract: Recently, it has been demonstrated that there is no
obvious correlation between DNA fragmentation (according to Terminal
dUTP Nick-End Labeling technique) and the severity of amyloid-beta (Aß)
deposition and neurofibrillary tangle (NFT) formation in patients
bearing mutations in presenilin 1[E280A]. Indeed, it was observed
in 10 out of 48 brain sections TUNEL-positive labeling, while none
showed classical apoptotic morphology. Based on these findings, we
were interested to determine whether cortical cells from temporal
and hippocampus post mortem brain sections die either by an
apoptotic or necrotic process in FAD-brain sections labeled TUNEL
positive compared with normal brain subjects labeled TUNEL-negative
using electron microscopy (EM). We found that FAD-brain sections
labeled TUNEL positive display the typical morphological
characteristics of cell death by necrosis i.e. the nuclear chromatin
form flocculent aggregates with poorly defined edges and electron
lucent (it does not appears black on EM); the chromatin aggregates
are irregularly scattered through the nucleus; mitochondria are
swoolen with flocculent matrix densities. No apoptotic bodies were
observed in any of the brain areas studied. These results may
indicate that necrosis is the most generalized cell death process
occurring in terminal PS1E280A brains and the DNA fragmentation of
nuclei labeled by TUNEL technique may reflect DNA vulnerability.
Thus, cell death by necrosis and the accompanying histopathological
observations such as severe deposition of amyloid plaques and NFTs,
severe gliosis, cortical depopulation, influx of lymphocytes
indicative of a chronic inflammation may have an important impact on
future therapeutic strategies in the treatment of PS1E280A patients.
Pages 417-425
Galván M, David JP, Delacourte A, Luna J and Mena R
Sequence of neurofibrillary changes in aging and Alzheimer's
disease: a confocal study with phospho-tau antibody, AD2
Abstract: In the present study, neurons of the entorhinal
cortex, hippocampus and frontal lobe from non-demented and
Alzheimer’s disease (AD) cases, were stained in order to study
neurofibrillary changes. We have used double immunolabelling with a
phosphorylation dependent monoclonal antibody (Mab) to tau, AD2, and
the histochemical dye thiazin red (TR). MAb AD2 specifically
recognizes phosphorylated Ser396 and Ser404, while TR shows binding
sites for amyloid-ß and tau when they are in fibrillar states. We
show a morphological sequence of changes in the development of
neurofibrillary tangles (NFTs), starting from mAb AD2 diffuse
labelling in non-NFT bearing cells recognized by mAb AD2, then going
throught two subtypes of intracellular NFTs, to a final stage as
extracellular-NFTs. Morphometric analysis of the density of AD2
immunoreactive structures showed the NFT density in hippocampus and
frontal lobe were the best parameters to differentiate normal aging
from AD. Densities of AD2 immunoreactive structures in hippocampus
and frontal lobe correlated with the Clinical Dementing Rating
score. Based upon the variety of appearances of immunoreactivity
displayed by mAb AD2, we were able to stage neurofibrillary changes
at the level of individual neurons and brain areas. Our results
demonstrate that the intensity of neurofibrillary changes in the
hippocampus as well as the extent of the degeneration process in
association areas differentiate normal aging from AD, and are well
correlated with cognitive impairment.
Page 427
Book Review: Decoding Darkness: The Search for the Genetic
Causes of Alzheimer’s Disease, Rudolph E. Tanzi and Ann B. Parson (Eds),
Perseus Publishing, Cambridge, Massachusetts, 2000, 320 pp. Reviewed
by Charles G. Glabe
Page 429
Book Review: Hard to Forget: An Alzheimer's Story, Charles P.
Pierce (Ed), Random House, New York, New York, 2000, 213 pp.
Reviewed by George M. Martin
Page 431
Book Review: Research and Practice in Alzheimer’s Disease,
Volume 3, Vellas B and Fitten LJ (Eds), Serdi Publisher, Paris,
France, 2000, 353 pp. Reviewed by Carlos Garcia
Page 433
Thomas G. Ohm
Eva Braak (1939-2000)
RETURN
TO INDEX
top |
|
an IOS Press publication
