Volume 3, Number
1, February 2001
Guest Editors:
Khalid Iqbal and Thomas Wisniewski
Special Memorial
Issue dedicated to Henry Wisniewski drawn from presentations made at
the World Alzheimer Congress 2000.
Page 1
George Perry
Forward
PDF
Page 3
Khalid Iqbal
Introduction
PDF
Page 5
Robert D. Terry
Henry M. Wisniewski - Fond Memories
PDF
Pages 7-22
Thomas Wisniewski
Henry M. Wisniewski M.D. Ph.D.
PDF
Pages 23-30
Yong Ji, Bruno Permanne, Einar M. Sigurdsson, David.M. Holtzman,
Thomas Wisniewski
Amyloid ß40/42 clearance across the blood-brain barrier following
intra-ventricular injections in wild-type, apoE knock-out and human
apoE3 or E4 expressing transgenic mice
PDF
An important event in the pathogenesis of Alzheimer’s disease (AD)
is the deposition of the amyloid ß (Aß)1-40 and 1-42 peptides in a
fibrillar form, with Aß42 typically having a greater propensity to
undergo this conformational change. A major risk factor for
late-onset AD is the inheritance of the apolipoprotein E (apoE) 4
allele. We previously proposed that apoE may function as a
“pathological chaperone” in the pathogenesis of AD (i.e,. modulate
the structure of Aß, promoting or stabilizing a ß-sheet
conformation), prior to the discovery of this linkage. Data from
apoE knockout / APPV717F mice, has shown that the presence of apoE
is necessary for cerebral amyloid formation, consistent with our
hypothesis. However, in APPV717F mice expressing human apoE3 or E4
early Aß deposition at 9 months is suppressed, but by 15 months both
human apoE expressing mice had significant fibrillar Aß deposits
with the apoE4 expressing mice having a 10 fold greater amyloid
burden. This and other data has suggested that apoE, in addition to
having a facilitating role in fibril formation, may also influence
clearance of Aß peptides. In order to address if apoE affects the
clearance of Aß peptides across the blood-brain barrier (BBB) and
whether there are differences in the clearance of Aß40 versus Aß42,
we performed stereotactic, intra-ventricular micro-injections of
Aß40, Aß42 or control peptides in wild-type, apoE knock-out (KO) or
human apoE3 or apoE4 expressing transgenic mice. We found that
consistent with other studies, Aß40 is rapidly cleared from the
brain across the BBB; however, Aß42 is cleared much less
effectively. This clearance of Aß peptides across the BBB does not
appear to be affected by apoE expression. This data suggests that
Aß42 production may favor amyloid deposition due to a reduced
clearance across the BBB, compared to Aß40. In addition, our
experiments support a role of apoE as a pathological chaperone, and
do not suggest an isotype specific role of apoE in Aß peptide
clearance from the CSF across the BBB.
Pages 31-40
Kurt A. Jellinger and Christine Stadelmann
Problems of Cell Death in Neurodegeneration and Alzheimer's
disease
PDF
Progressive cell loss in specific neuronal populations is a
pathological hallmark of neurodegenerative diseases, but its
mechanisms remain unresolved. Apoptosis or alternative pathways of
neuronal death have been discussed in Alzheimer disease (AD) and
other disorders. However, DNA fragmentation in human brain as a sign
of neuronal injury is too frequent to account for the continuous
loss in these slowly progressive diseases. In autopsy cases of AD,
Parkinson´s disease (PD), related disorders, and age-matched
controls, DNA fragmentation using the TUNEL method and an array of
apoptosis-related proteins (ARP), proto-oncogenes, and activated
caspase 3, the key enzyme of late-stage apoptosis, were examined. In
AD, a considerable number of hippocampal neurons and glial cells
showed DNA fragmentation with a 3- to 6-fold increase related to
amyloid deposits and neurofibrillary tangles, but only one in 2.600
to 5.650 neurons displayed apoptotic morphology and cytoplasmic
immunoreactivity for activated caspase 3, whereas no neurons were
labeled in age-matched controls. Caspase 3 immunoreactivity was seen
in granules of cells with granulovacuolar degeneration, in around
25% co-localized with early cytoplasmic deposition of tau-protein.
In progressive supranuclear palsy, only single neurons but
oligodendrocytes in brainstem, around 25% with tau-inclusions, were
TUNEL-positive and expressed both ARPs and activated caspase 3. In
PD, dementia with Lewy bodies, and multisystem atrophy (MSA),
TUNEL-positivity and expression of ARPs or activated caspase 3 were
only seen in microglia and oligodendrocytes with cytoplasmic
inclusions in MSA, but not in neurons. These data provide evidence
for extremely rare apoptotic neuronal death in AD and PSP compatible
with the progression of neuronal degeneration in these chronic
diseases. Apoptosis mainly involves reactive microglia and
oligodendroglia, the latter occasionally involved by deposits of
insoluble fibrillary proteins, while alternative mechanisms of
neuronal death may occur. Susceptible cell populations in a
proapoptotic environment, particularly in AD, show increased
vulnerability towards metabolic or other noxious factors, with
autophagy as a possible protective mechanism in early stages of
programmed cell death. The intracellular cascade leading to cell
death still awaits elucidation.
Pages 41-48
Jin-Jing Pei, Eva Braak, Heiko Braak, Inge Grundke-Iqbal, Khalid
Iqbal, Bengt Winblad, Richard F. Cowburn
Localization of active forms of C-jun kinase (JNK) and p38 kinase
in Alzheimer’s disease brains at different stages of neurofibrillary
degeneration
PDF
The principal protein component of paired helical filaments (PHFs)
in Alzheimer disease is abnormally hyperphosphorylated tau
(PHF-tau). The stress activated protein kinases JNK and p38 have
been shown to phosphorylate tau at some sites only seen in PHF-tau.
If JNK and p38 are involved in the abnormal hyperphosphorylation of
tau, they should be activated in neurons undergoing neurofibrillary
degeneration. In the present study, we determined the intracellular
and regional distribution of the active forms of JNK and p38 kinase
in entorhinal, hippocampal, and temporal cortices of brains staged
for neurofibrillary changes according to Braak and Braak. Neurons
with tangle-like inclusions positive for active forms of JNK and p38
kinase were found to appear first in the Pre-a layer of the
entorhinal cortex, and then extend into other brain regions
co-incident with the progressive sequence of neurofibrillary
changes. The intraneuronal accumulation of active forms of JNK and
p38 kinase appeared to precede the deposition of amyloid in the
extracellular space. These data indicate that increased activation
of the stress related kinases JNK and p38 occurs very early in the
disease and might be involved in the intraneuronal protein
phosphorylation/dephosphorylation imbalance that leads to
neurofibrillary degeneration in Alzheimer disease.
Pages 49-57
Jerzy Wegiel, Maciej Bobinskia, Michal Tarnawskia, Jerzy
Dziewiatkowskib, Eirene Popovitcha, Margaret Bobinskia, Boleslaw
Lachc, Barry Reisbergd, Douglas C. Millere, Susan de Santid, Mony J.
de Leond
Shift from fibrillar to nonfibrillar Aß deposits in the neocortex
of subjects with Alzheimer disease
PDF
A morphometric study of amyloid-ß-positive plaques in the neocortex
of eight non-demented people from 68 to 82 years of age and 17
subjects with late-stage Alzheimer disease (GDS stage 7/FAST stages
7a-f) from 73 to 93 years of age shows a shift from prevalence of
fibrillar plaques to prevalence of nonfibrillar plaques. In the
aged, non-demented subjects, about 4/mm2 plaques are detectable in
the neocortex, and the majority are fibrillar plaques. Specifically,
64% of plaques in the neocortex of the normal aged subjects were
found to be classical fibrillar and Thioflavin-S-positive bright
primitive plaques. A lower percentage of pale primitive plaques
(35%) and diffuse plaques (1%) was observed, reflecting the
relatively small proportion of plaques that are poor in thioflavin
S-positive fibrils. The numerical density of plaques in the severe
stage of AD increases to about 41/mm2. Severely demented subjects
appear to maintain an active process of fibrillar plaque formation.
This is reflected in the presence of 3% fibrillar classical and 27%
bright primitive plaques. Severely demented subjects also manifest
plaque degradation, reflected in the presence of 22% pale primitive
and 48% diffuse-like Thioflavin S-negative plaques. Comparable
percentages of classical fibrillar plaques in non-demented subjects
and in the end stage of disease suggest that once activated, the
process of fibrillar plaque formation persists at a somewhat stable
rate during the whole course of brain amyloidosis.
Pages 59-63
Christian Bancher
From counting neurons to the preclinical diagnosis of Alzheimer’s
disease: The fruits of collaborative work with Dr. Henryk M.
Wisniewski
PDF
This article is a review of scientific work on Alzheimer
neurofibrillary degeneration and Aß-amyloidosis that was done in
collaboration with Dr. Henryk Wisniewski, in part at the Institute
for Basic Research in Developmental Disabilities. Our work on
paired helical filaments and the tau protein spans from basic
immunocytochemical analyses of brain tissue to clinical application
as a biological marker used in diagnostic tests. Even though only
a small part of Dr. Wisniewski’s scientific oeuvre, these data
illustrate how a great scientist opens the field to his student,
collaborator and friend, how basic science can evolve, and how
results can be applied in clinical practice to the benefit of our
patients.
Pages 65-73
Jorge Ghiso and Blas Frangione
Cerebral amyloidosis, amyloid angiopathy, and their relationship
to stroke and dementia
PDF
Cerebral amyloid angiopathy (CAA) is the common term used to define
the deposition of amyloid in the walls of medium- and small-size
leptomeningeal and cortical arteries, arterioles and, less
frequently, capillaries and veins. CAA is an important cause of
cerebral hemorrhages although it may also lead to ischemic
infarction and dementia. It is a feature commonly associated with
normal aging, Alzheimer disease (AD), Down syndrome (DS), and
Sporadic Cerebral Amyloid Angiopathy. Familial conditions in which
amyloid is chiefly deposited as CAA include hereditary cerebral
hemorrhage with amyloidosis of Icelandic type (HCHWA-I), familial
CAA related to Aß variants, including hereditary cerebral hemorrhage
with amyloidosis of Dutch origin (HCHWA-D), the
transthyretin-related meningocerebrovascular amyloidosis of
Hungarian and Ohio kindreds, the gelsolin-related spinal and
cerebral amyloid angiopathy, familial PrP-CAA, and the recently
described chromosome 13 familial dementia in British and Danish
kindreds. This review focuses on the various molecules and genetic
variants that target the cerebral vessel walls producing clinical
features related to stroke and/or dementia, and discusses the
potential role of amyloid in the mechanism of neurodegeneration.
Pages 75-81
Dennis J. Selkoe
Alzheimer's disease results from the cerebral accumulation and
cytotoxicity of amyloid ß-protein: A reanalysis of a therapeutic
hypothesis
PDF
The progressive cognitive and behavioral symptoms which characterize
Alzheimer's disease (AD) derive from profound functional and
structural changes observed in neurons, their processes and
synapses, and the microgliosis and astrocytosis which accompany
these changes. This multicellular dysfunction appears to represent
a common cytopathological response to several distinct genetic
defects and perhaps also to certain environmental precipitants that
remain poorly understood. In short, AD is actually a syndrome in
which multiple molecular etiologies can trigger a somewhat varied
but largely stereotyped pathogenetic cascade. From this
perspective, AD resembles other common, multigenic degenerative
pathologies of late life, such as atherosclerosis. Because the AD
syndrome has multiple molecular causes and a gradual, chronic
evolution, one may anticipate several distinct classes of
therapeutic molecules that could interfere with one or another step
in the disease cascade.
Pages 83-86
Colin L Masters and Konrad Beyreuther
Henryk M. Wisniewski and the amyloid theory of Alzheimer’s
disease
PDF
The amyloid theory of Alzheimer’s disease (AD) is now the dominant
paradigm for the etiology of this particular neurodegenerative
disorder, and Henryk Wisniewski played a major role in its
elaboration. Together with Robert Terry, in the early 1970’s, they
were in a position to take advantage of the electron microscope to
give a fine structural account of the appearances of Aß amyloid
deposition in the AD brain. Wisniewski brought his characteristic
flair to these descriptive analyses, best summarised in a review
article published in 1973 (Wisniewski and Terry, 1973). That review
has come to represent the watershed between the classic morphologic
approach (commencing with Bloqc and Marinesco in 1892) and the
current molecular biological era. It is worth re-reading in detail,
since it sets out clearly many of the paradoxes of Aß deposition
that still require clarification. Let’s summarize Wisniewski’s
analysis of the amyloid theory as it stood in 1973, and then see
where his ideas have led us today.
Pages 87-95
Pierluigi Gambetti, Piero Parchi, Sabina Capellari, Claudio Russo,
Massimo Tabaton, Jan K. Teller, Shu G. Chen
Mechanisms of Phenotypic Heterogeneity in Prion, Alzheimer and
Other Conformational Diseases
PDF
One of the challenges faced by clinicians and pathologists is
dealing with the variability of the clinical signs and of the
pathological changes that are associated with diseases. The truism
that two patients with the same disease are never identical poses no
serious diagnostic problems under most circumstances. However,
there are diseases that present considerable variability in their
clinical and pathological phenotype, which not only makes the
diagnosis difficult but also raises the issue of the mechanisms that
regulate it.
Pages 97-107
Ralph A. Nixon, Paul M. Matthews, Anne M. Cataldo
The neuronal endosomal-lysosomal system in Alzheimer’s disease
PDF
Robust activation of the neuronal lysosomal system and other
cellular pathways converging on the lysosome, such as the endocytic
and autophagic pathways, are prominent neuropathological features of
Alzheimer’s disease. Disturbances of the neuronal endocytic
pathway, which are one of the earliest known intracellular changes
occurring in Alzheimer’s disease and Down syndrome, provide insight
into how b-amyloidogenesis might be promoted in sporadic Alzheimer’s
disease, the most prevalent and least well understood form of the
disease. Lysosomal system dysfunction historically has been linked
to neurodegeneration. New data now directly implicate lysosomal
cathepsins as proteases capable of initiating, as well as executing,
cell death programs in certain pathologic states. These and other
studies support the view that the progressive alterations of
lysosomal system function observed during Alzheimer’s disease have
broad relevance to the neurodegenerative processes occurring during
the disease.
Pages 109-116
John Hardy
The Genetic Causes of Neurodegenerative Diseases
PDF
With the application of molecular genetics, we are now beginning to
understand the etiology and the early stages of pathogenesis of the
major neurodegenerative diseases, including Alzheimer’s disease,
Parkinson’s disease, Pick’s disease and Progressive Supranuclear
Palsy. Surprisingly, these studies are showing that these diseases
share pathogenic mechanisms which involve tau or synuclein
aggregation. In this article, I review the progress in the
molecular genetic analysis of these major neurodegenerative diseases
and discuss how they are related to each other.
Pages 117-119
John Q. Trojanowski and Virginia M.-Y. Lee
Brain degeneration linked to "fatal attractions" of proteins in
Alzheimer's disease and related disorders
PDF
A common mechanistic theme shared by Alzheimer’s disease (AD) and
many other seemingly unrelated neurodegenerative disorders is
emerging from accelerating research progress in the last few years
which is beginning to dispel the pessimistic assumption that each
phenotypically and genotypically distinct sporadic as well as
hereditary degenerative disorder of the aging central nervous system
(CNS) will require a different, disease-specific therapeutic
intervention. Specifically, a growing body of data from different
lines of investigation has made it increasingly clear that a large
number of diverse neuropsychiatric degenerative disorders are
characterized neuropathologically by intracellular and/or
extracellular filamentous lesions and that these lesions are
implicated mechanistically in the onset/progression of disease in
affected patients.
Pages 121-129
Eliezer Masliah
Recent advances in the understanding of the role of synaptic
proteins in Alzheimer’s disease and other neurodegenerative
disorders.
PDF
Synaptic damage is an early pathological event common to many
neurodegenerative disorders such as Alzheimer’s disease (AD) and is
the best correlate to the cognitive impairment. Several molecules
involved in AD and in other neurodegenerative disorders play an
important role in synaptic function and when misfolded aggregate and
form amyloid fibrils. Synaptic proteins with an amyloid domain
include amyloid ß-protein precursor, prion protein, huntingtin,
ataxin-1 and alpha-synuclein. Two of the possible mechanisms by
which alterations in synaptic proteins lead to synapse damage are:
1) misfolded or aggregated synaptic molecules have lost their normal
function and/or 2) they have gained a toxic capacity. Recent
studies support the possibility that while oligomers are toxic,
polymers might be inactive. The mechanisms by which oligomers
trigger synapse loss could be related to their ability to triggers
stress signals once they enter the nucleus and/or accumulate at the
endoplasmic reticulum.
Pages 131-157
Ronald Strohmeyer and Joseph Rogers
Molecular and cellular mediators of Alzheimer’s disease
inflammation
PDF
A wide range of inflammatory mediators has been demonstrated in the
Alzheimer’s disease (AD) brain during the past 15 years. Questions
nonetheless remain, including even the designation of AD
inflammatory mechanisms as a true inflammatory response. Like
multiple sclerosis, the cardinal signs of peripheral inflammation,
the "rubor et tumor cum calore et dolore" (redness and swelling with
heat and pain) that Cornelius Celsus defined as criteria 2000 years
ago, are not present in AD. Indeed, AD inflammation does not appear
to include even cell-mediated humoral lymphocyte responses, as
multiple sclerosis clearly does. Rather, our current understanding
of AD inflammation suggests that it is an endogenously-mediated,
localized reaction, an innate inflammatory response similar to that
mounted in the periphery when localized tissue damage and the
chronic deposition of highly insoluble, abnormal material occurs.
Such primarily macrophage-mediated reactions have been classed as
inflammatory for over a century, and that designation, with glia as
the brain intermediaries, certainly should hold for AD.
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