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
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Page 3
Khalid Iqbal
Introduction
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Page 5
Robert D. Terry
Henry M. Wisniewski - Fond Memories
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Pages 7-22
Thomas Wisniewski
Henry M. Wisniewski M.D. Ph.D.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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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