Journal of Alzheimer's Disease - Volume 9, issue s3

Authors: Masliah, Eliezer | Crews, Leslie | Hansen, Lawrence

Article Type: Research Article

Abstract: Cognitive functioning is dependent on synapse density in the brain. Factors modulating synapse density might include the balance between synaptic pruning and sprouting. Loss of synapses during aging might explain cognitive decline and while previous reports have suggested a 10–15% synapse loss occurs during the normal aging process, more recent studies have found that decline in synaptic density only occurs after 65 years of age. In this context, the main objective of this manuscript is to discuss the findings of our 1993 study in light of more recent studies in aging, synapses and Alzheimer's disease.

Keywords: Alzheimer's disease, amyloid, synapse loss, synaptic plasticity, AβPP

DOI: 10.3233/JAD-2006-9S311

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 91-99, 2006

Authors: Scheff, Stephen W. | Price, Douglas A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive disorder that is characterized by the accumulation of neuropathologic lesions and neurochemical alterations. Ultrastructural investigations in many association regions of the neocortex and the hippocampal dentate gyrus have demonstrated a disease-related decline in numerical synaptic density. This decline in brain connectivity occurs early in the disease process and strongly correlates with the cognitive decline observed in AD. The synapse loss does not appear to be an inevitable consequence of the aging process. This article reviews the ultrastructural studies assessing AD-related synaptic loss and the possible compensatory changes in the synaptic complex that occur as …a result of the loss in brain connectivity. Show more

Keywords: Plasticity, limbic, cognition, synapse, ultrastructure

DOI: 10.3233/JAD-2006-9S312

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 101-115, 2006

Authors: Terry, Robert D.

Article Type: Research Article

Abstract: This brief paper reviews the work on dementia by the Neuropathology group at the Einstein College of Medicine and later at the University of California, San Diego, from the time of our first approaches to Alzheimer Disease in 1959. The electron microscope studies concerned the tangle (got it wrong) and then the plaque (got it right). Lysosomes and active microglia were noted in the plaques. Axoplasmic transport was suggested to be abnormal. We studied the plaques in old dogs and old monkeys, and then went on to use image analysis to count neurons in the neocortex of Alzheimer cases and …in examples of normal aging. Later in San Diego we quantified presynaptic boutons and recognized their loss as the major direct cause of dementia. Many collaborators including Henry Wisniewski participated in these early attempts to understand the disease. Show more

DOI: 10.3233/JAD-2006-9S313

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 117-119, 2006

Authors: Ashe, Karen H.

Article Type: Research Article

Abstract: Understanding the pathophysiology and treatment of Alzheimer's disease is vitally important. Alzheimer's disease threatens to affect currently at least 30% of all individuals currently alive in the 12 most financially developed countries, unless interventions are discovered to prevent or treat the disease. Although memory loss is the cardinal symptom of Alzheimer's disease, the pathophysiological mechanisms leading to cognitive deficits are poorly understood. It is difficult to address this problem in human studies, and impossible in cultured cells. Therefore, animal models are needed to elucidate the molecular mechanisms leading to dementia. A large number of animal models have focussed upon the …role of amyloid plaques in the pathogenesis of Alzheimer's disease, because amyloid plaques are an essential diagnostic feature of the disease. However, the mechanism by which amyloid plaques or their principal molecular constituent, the amyloid-β protein (Aβ), disrupt cognitive function is not well understood. Herein, I describe my perspective on what we have learned about how Aβ impairs memory from research on Alzheimer's disease in mice and rats. Show more

Keywords: Memory, transgenic, mice, rats, Morris water maze, operant behavioral task, Aβ oligomers

DOI: 10.3233/JAD-2006-9S314

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 123-126, 2006

Authors: Tabaton, Massimo | Gambetti, Pierluigi

Article Type: Research Article

Abstract: Researchers since the 1990s have predominantly focused on the amyloid hypothesis and the formation of amyloid fibrils as the culprit behind AD when we began working on soluble Aβ (sAβ). Unexpectedly, this work produced several novel findings. First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble Aβ in AD; secondly, that all sAβ species belong to the 42 form and the sAβ x-40 species is virtually absent in AD parenchyma; thirdly, that Aβ42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains. The later observation that sAβ 42 species is present …in amyloid β protein precursor (AβPP) over-expressing brains of patients with Down syndrome in prenatal and early postnatal development argued that sAβ is present in brain in abnormal conditions and that its appearance seeds Aβ aggregation and accumulation. Although the sAβ we described in intact brain tissue appeared to match the soluble Aβ oligomers detected in cell media, which were subsequently shown to be the most toxic form of Aβ, our research has been virtually ignored by the Alzheimer field. It continues nevertheless. Recently we demonstrated that the sAβ species present in physiologically aging brains are different from those present in brains with sporadic AD as the latter form oligomers more quickly, are more toxic to neurons, and produce more severe membrane damage than the Aβ species associated with normal brain aging. Furthermore, in familial AD, the composition of soluble Aβ appears to dictate distinctive features of the disease phenotype introducing the notion of Aβ strains, a concept well established in prion diseases. Show more

DOI: 10.3233/JAD-2006-9S315

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 127-132, 2006

Authors: Games, Dora | Buttini, Manuel | Kobayashi, Dione | Schenk, Dale | Seubert, Peter

Article Type: Research Article

Abstract: Progress in understanding and treating Alzheimer's disease (AD) has been tremendously bolstered by the era of transgenic models of AD. The identification of disease-causing mutations in proteins such as amyloid-β precursor protein (βAPP) and presenilin1 (PS1), together with the discovery of other high risk factors (e.g., Apolipoprotein E4), as well as pathogenic mutations in the tau protein has led to the creation of several transgenic mice, including those expressing bi- and tri-genic constructs. Each model has unique pathologies that provide insights into disease mechanisms and interactive features of neuropathologic cascades. More importantly, therapeutic hypotheses are now testable in a manner …unheard of less than 15 years ago. The wealth of new approaches currently in clinical and preclinical evaluations can be directly attributed to the impact of these animals on our ability to model relevant aspects of the disease. As a result, we may see containment or even the elimination of AD in the near future as a direct consequence of these advances. Show more

Keywords: Transgenic mice, βAPP, amyloid-β, Alzheimer's disease, plaques, pathology, therapeutic, immunization

DOI: 10.3233/JAD-2006-9S316

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 133-149, 2006

Authors: Hardy, John

Article Type: Research Article

Abstract: Here I recap the scientific and personal background of the delineation of the amyloid cascade hypothesis for Alzheimer's disease that I wrote with Gerry Higgins and the events leading to the writing of that influential review.

DOI: 10.3233/JAD-2006-9S317

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 151-153, 2006

Authors: Masters, Colin L. | Beyreuther, Konrad

Article Type: Research Article

Abstract: Many participants played a role in discovering the composition and sequence of the Aβ amyloid of Alzheimer's disease. This sequence enabled the cloning of the amyloid precursor protein (APP), which elucidated its proteolytic origin from the membrane of neurons. The proteolytic enzymes which process APP and the Aβ fragment itself are now the prime validated drug targets for therapeutic intervention.

DOI: 10.3233/JAD-2006-9S318

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 155-161, 2006

Authors: Selkoe, Dennis J.

Article Type: Research Article

Abstract: In the twenty years since George Glenner identified the amyloid β-protein (Aβ), advances in understanding the biochemical pathology, genetics and cell biology of Alzheimer's disease have led to a detailed molecular hypothesis for the genesis of AD and brought us into human trials of anti-amyloid agents. The ability to study Aβ dynamically in cultured cells and in vivo derives from the recognition in 1992 that Aβ is a normal product of cellular metabolism throughout life and circulates as a soluble peptide in biological fluids. Here, I review the background underlying this discovery and then discuss its implications for research on …Alzheimer's disease, particularly for the development of disease-modifying therapies. Show more

Keywords: Amyloid β-protein, APP, secretases, Alzheimer's disease, drug discovery

DOI: 10.3233/JAD-2006-9S319

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 163-168, 2006

Authors: Avila, Jesús

Article Type: Research Article

Abstract: In this volume we commemorate the centennial of Alois Alzheimer's discovery of what was later known as Alzheimer's disease, named by Alzheimer's mentor, Emil Kraepelin [1]. In a much more low level, our group remember in this issue a paper published twenty years ago. In that paper it was described that tau can self-polymerize and, at that time, it suggested that tau was not only a component of Alzheimer paired helical filaments, as indicated some months earlier during that year, 1986, but that it was the main component of Alzheimer paired helical filaments.

Keywords: Alzheimer disease, paired helical filament, phosphorylation, tau

DOI: 10.3233/JAD-2006-9S320

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 171-175, 2006

Authors: Brion, Jean-Pierre

Article Type: Research Article

Abstract: Neurofibrillary tangles are one of the neuropathological hallmark of Alzheimer's disease, described early as part of the pathological criteria of the disease. Ultrastuctural studies in the sixties showed their unusual features but their molecular composition was not unraveled before the mid-eighties. Initial biochemical studies suggested that they were composed of modified unidentified brain proteins, and several immunocytochemical studies suggested that they contained polypeptides cross-reactive with antibodies to cytoskeletal proteins. In 1985, we demonstrated that neurofibrillary tangles were immunolabelled by antibodies to the microtubule-associated protein tau and that antibodies raised to neurofibrillary tangles cross-reacted with tau proteins. These results were soon …confirmed independently in several laboratories. Further studies were devoted to the analysis of tau post-translationnal modifications in the affected tissues and in cellular and animal models. Show more

Keywords: Alzheimer's disease, neurofibrillary tangles, tau proteins, microtubules, phosphorylation

DOI: 10.3233/JAD-2006-9S321

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 177-185, 2006

Authors: Delacourte, André

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a very frequent brain pathology of the elderly, with an etiology by far more complicated than thought in the nineties. In particular, the complexity comes from the coexistence of two degenerating processes, tau aggregation and Aβ deposition, that affect polymodal association brain areas, a feature never observed in non-human primates and difficult to model. Genetic studies have shown that AβPP plays a central role in familial and sporadic AD, but the role of tau has been for a long time understated. To apprehend this role, we have developed a spatio-temporal analysis of tauopathy in many brain …areas of hundreds of non-demented and demented patients. This prospective and multidisciplinary study showed us that tauopathy always progresses in the brain along a very precise and invariable pathway, from the entorhinal then hippocampal formation to polymodal association areas to end in primary regions and in many subcortical areas. The cognitive impairment follows exactly the progression of the affected brain regions. In strict parallelism, neocortical Aβ deposits increase in quantity and heterogeneity, suggesting a direct link between both neurodegenerative processes. Altogether, our molecular study suggests that AD is a tauopathy fueled by AβPP dysfunction. Restoring AβPP loss of function seems to be the most efficient therapeutic approach. Show more

DOI: 10.3233/JAD-2006-9S322

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 187-194, 2006

Authors: Goedert, Michel | Klug, Aaron | Crowther, R. Anthony

Article Type: Research Article

Abstract: In 1906, Alzheimer described the clinical and neuropathological characteristics of the disease that was subsequently named after him. Although the paired helical filament was identified as the major component of the neurofibrillary pathology of Alzheimer's disease in 1963, its molecular composition was only uncovered in the 1980s. In 1988, work at the MRC Laboratory of Molecular Biology in Cambridge (UK) provided direct proof that tau protein is an integral component of the paired helical filament. The paper highlighted here [Goedert M., Wischik C.M., Crowther R.A., Walker J.E. and Klug A. (1988) Cloning and sequencing of a core protein of the …paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 85, 4051–4055] also reported the first sequerce of a human tau isoform and paved the way for the identification of the six brain tau isoforms that are expressed by alternative mRNA splicing from a single gene. By the early 1990s, it was clear that tau protein is the major component of the paired helical filament and that the latter is made of all six tau isoforms, each full-length and hyperphosphorylated. Show more

Keywords: Alzheimer disease, neurofibrillary tangles, paired helical filament, tau

DOI: 10.3233/JAD-2006-9S323

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 195-207, 2006

Authors: Ihara, Yasuo

Article Type: Research Article

Abstract: Neurofibrillary tangles, one of the hallmarks of Alzheimer's disease, had been a target of modern neuropathology based on electron microscopy. In 1960s their unit fibrils were found to be paired helical filaments (PHF), the unique appearance of which attracted many researchers to their nature. In the late 1970s, a keen interest in their constituents at the molecular levels had increasingly grown, but electron microscopic approach failed to address the issue. I describe here what was going on at the turning point when electron microscopic study yielded immunocytochemical approach and direct characterization by isolation, with some emphasis on the situation in …Japan. Personal memories are provided about Dr Selkoe's lab (1981–1982) in Mailman Research Center, Belmont, Boston, where we encountered a series of remarkable properties of PHF. How insolubility of PHF, and smearing on the blot was found is described. Show more

DOI: 10.3233/JAD-2006-9S324

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 209-217, 2006

Authors: Iqbal, Khalid | Grundke-Iqbal, Inge

Article Type: Research Article

Abstract: Alzheimer disease was described by Alois Alzheimer in 1907, but it was not until ∼ 60–70 years later that any new significant developments were reported on the pathology of this disease. The discoveries that laid down the foundation for the exciting research that has been carried out during the last ∼ 20 years and that have significantly enhanced our understanding of the disease are the ultrastructure of neurofibrillary tangles and neuritic (senile) plaques, the clinical-pathological correlation of these lesions to the presence of dementia, and the bulk isolation and protein composition of paired helical filaments and plaque amyloid. We discovered …tau as the major protein subunit of paired helical filaments/neurofibrillary tangles, the abnormal hyperphosphorylation of this protein in this lesion and in Alzheimer brain cytosol and the gain of toxic function by the cytosolic abnormally hyperphosphorylated tau in Alzheimer brain. Here we present a personal historical account of the work in our laboratories that led, in 1986, to the discoveries of tau and its abnormal hyperphosphorylation in paired helical filaments and Alzheimer brain cytosol. This article also describes several major findings which subsequently resulted from the abnormal hyperphosphorylation of tau and in a large part account for the current understanding of the role of this lesion in Alzheimer disease and other tauopathies. Show more

Keywords: Tau, abnormally hyperphosphorylated tau, neurofibrillary tangles, paired helical filaments, self-assembly of tau, protein phosphatase-2A, protein phosphatase-1, microtubule assembly, MAP1, MAP2, glycogen synthase kinase-3β, cyclin-dependent protein kinase-5, protein kinase A

DOI: 10.3233/JAD-2006-9S325

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 219-242, 2006

Authors: Johnson, Gail V.W.

Article Type: Research Article

Abstract: In 1992 little was known about the specific protein kinases that phosphorylate tau and the proteases that regulate tau turnover. Although we had already demonstrated that tau was a substrate of the calcium-activated protease calpain (Johnson et al. (1989), Biochem Biophys Res Commun 163, 1505–1511), our publication entitled, “Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain” (Litersky and Johnson (1992), J Biol Chem 267, 1563–1568) was the first demonstration that phosphorylation by a specific kinase could inhibit the proteolysis of tau by calpain. At the time these findings suggested that the abnormal phosphorylation of tau in …Alzheimer's disease brain could result in impaired tau turnover and thus result in an abnormal accumulation of the protein that could contribute to the formation of pathological lesions. Since this initial finding, much has been learned about the proteolysis of tau, not only by calpain, but by other proteases as well. However, much remains unknown about how phosphorylation regulates tau turnover in vivo and the specific proteases involved. In this article we give a brief history of our initial findings and then discuss subsequent studies from our laboratory, as well as others, on tau proteolysis and modulation by phosphorylation and how these findings contribute to our understanding of the posttranslational processing of tau in Alzheimer's disease. Show more

DOI: 10.3233/JAD-2006-9S326

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 243-250, 2006

Authors: Kosik, Kenneth S.

Article Type: Research Article

Abstract: Studies of the tau protein and its pathological fate as a neurofibrillary tangle have been a pillar of Alzheimer's disease research. The understanding of the fundamental position that tau occupies in the disease cascade is a tribute to an international group of scientists who brought rigor, candid assessments of data, and critical thinking to the problem. The tau pathway winds its way from astute clinical observations to pathological correlations, from molecular and cellular experiments to mining informatic data, and from animal behavior to the biophysics of protein structure. For most the vindication of this tireless effort will come from tau-based …therapies; but for others the remarkable biology revealed by the Alzheimer disease process has been its own reward. Show more

DOI: 10.3233/JAD-2006-9S327

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 251-256, 2006

Authors: Lee, Virginia M.-Y. | Trojanowski, John Q.

Article Type: Research Article

Abstract: The landmark description of neurofibrillary tangles (NFTs) and senile plaques as the pathological hallmarks of an unusual form of dementia 100 years ago by Alois Alzheimer launched the quest to understand a neurodegenerative disorder that now has become a scourge in the 21st Century due to the unprecedented increase in human life expectancy since 1900. Indeed, while there are many benefits to individuals and society as a whole that will accrue from the remarkable gains in longevity since 1900, the risk of developing Alzheimer's disease (AD) increases exponentially with advancing age beyond the 7th decade of life. Hence, the prevalence …of AD will rise inexorably in the coming decades unless effective interventions are developed to delay the onset or progression of AD. Widespread international recognition of the urgency of this problem has accelerated research to discover meaningful therapies for AD, and growing evidence implicates impairments of axonal transport in mechanisms underlying AD due to pathological alterations in tau, the building block proteins of NFTs. This brief review summarizes insights into mechanisms whereby pathological alterations in tau impair axonal transport resulting in neurodegeneration and how these insights are being exploited now to develop novel therapeutic interventions for the treatment of AD. Show more

Keywords: Tau, neurofibrillary tangles, microtubules, taxol

DOI: 10.3233/JAD-2006-9S328

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 257-262, 2006

Authors: Davies, Peter

Article Type: Research Article

Abstract: The invitation to contribute to the issue marking the 100th anniversary of Alzheimer's disease gave me pause to reflect on the significant milestones in my own research. This brief and personal description of my laboratory's search for the cause of cell dysfunction and death in Alzheimer's disease marks only highlights, and my apologies to those whose work I have passed over.

DOI: 10.3233/JAD-2006-9S329

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 265-269, 2006

Authors: McGeer, Patrick L. | Rogers, Joseph | McGeer, Edith G.

Article Type: Research Article

Abstract: Two basic discoveries have spurred research into inflammation as a driving force in the pathology of Alzheimer disease (AD). The first was the identification of activated microglia in association with the lesions. The second was the finding that rheumatoid arthritics were relatively spared from the disease. These findings spurred the first pilot trial of a classical NSAID in the treatment of AD. This trial showed promise for indomethacin as a useful therapeutic agent but appropriate follow up trials have not been done. However, more than 20 epidemiological studies have since been conducted showing a sparing effect for antiinflammatories in AD, …including four which specifically addressed the use of classical NSAIDs. Other key findings linking inflammation to AD pathology are the identification of activated complement fragments, including the membrane attack complex, as well as inflammatory cytokines in association with the lesions. In vitro, activated microglia release factors which are toxic to neurons, and these can be partially blocked by NSAIDs. Future directions should include a search for other inflammatory mediators in AD and exploitation of current knowledge to improve available treatments. Show more

Keywords: NSAID, indomethacin, complement, membrane attack complex, immunohistochemistry, reactive microglia

DOI: 10.3233/JAD-2006-9S330

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 271-276, 2006

Authors: Nixon, Ralph A. | Cataldo, Anne M.

Article Type: Research Article

Abstract: The identification of cathepsins in amyloid-β plaques revealed broad dysfunction of the lysosomal system in Alzheimer's disease (AD). Coinciding with the discovery that proteolysis is required to generate the Aβ-peptide, these findings heralded an era of intense investigation on proteases in neurodegeneration. This review traces lysosomal system pathology from its early characterization to its origins within two pathways leading to the lysosome, the endocytic and autophagic pathways. An understanding has grown about how these two pathways are adversely influenced by normal brain aging and by genetic and environmental risk factors for AD, resulting in increased susceptibility of neurons to injury, …amyloidogenesis, and neurodegeneration. Show more

Keywords: Amyloid-β, cathepsin, apoptosis, endosome, autophagy, necrosis, Alzheimer's disease, protease, endocytosis

DOI: 10.3233/JAD-2006-9S331

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 277-289, 2006

Authors: Perl, Daniel P. | Moalem, Sharon

Article Type: Research Article

Abstract: It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled with x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing …neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesions in Alzheimer's disease and other related disorders. Show more

DOI: 10.3233/JAD-2006-9S332

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 291-300, 2006

Authors: Perry, George

Article Type: Research Article

Abstract: Dissection of neurofibrillary tangles has been confounded by the insolubility of their fibers. While the majority of biochemical studies have considered τ filaments equivalent to neurofibrillary tangles, they forget that the former are soluble and the latter completely resistant to solvents. What, then, accounts for the insolubility of neurofibrillary tangles while τ filaments are soluble? Investigation of these distinctions played a critical role in our findings on proteolytic abnormalities and oxidative stress.

DOI: 10.3233/JAD-2006-9S333

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 301-304, 2006

Authors: Smith, Mark A.

Article Type: Research Article

Abstract: The role of oxidative stress in the pathogenesis of Alzheimer disease has gone from epiphenomena to phenomena. This transition, from disregarded to accepted theory, started in the early-mid 1990s and was accelerated by a number of reports in the literature showing that redox-active sources of transition metals, such as iron, were increased in the brain at early stages of disease. As such, it became apparent that not only was there damage but, more importantly, the machinery to exact such damage was ever present. In this review, the author chronicles his personal perspective on the past, present, and future of oxidative …stress in Alzheimer disease. Show more

DOI: 10.3233/JAD-2006-9S334

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 305-308, 2006

Authors: Takashima, Akihiko

Article Type: Research Article

Abstract: Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3β is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3β has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3β was involved in amyloid-β (Aβ)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional …investigations showing that Aβ activates GSK-3β through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Aβ-activated GSK-3β induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3β can induce memory deficits in vivo; and that inhibition of GSK-3α (an isoform of GSK-3β) reduces Aβ production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease. Show more

Keywords: GSK-3β, NFT, Aβ, AD, tauopathy

DOI: 10.3233/JAD-2006-9S335

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 309-317, 2006

Authors: van Leeuwen, F.W. | Hol, E.M. | Fischer, D.F.

Article Type: Research Article

Abstract: Neuronal homeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the ubiquitin-proteasome system (UPS) and discovered a frameshift protein for ubiquitin (UBB+1 ), that accumulates in the neuritic plaques and tangles in patients with Alzheimer's disease (AD). UBB+1 , unable to tag proteins to be degraded, has been shown to be a substrate for ubiquitination and subsequent proteasomal degradation. If UBB+1 is accumulated, it inhibits the proteasome, which may result in neuronal death. We showed that UBB+1 …is also present in other tauopathies (e.g. Pick's disease) and in several polyglutamine diseases, but remarkably not in synucleinopathies (e.g. Parkinson's disease). Accumulation of UBB+1 -being a reporter for proteasomal dysfunctioning- thus differentiates between these conformational diseases. The accumulation of UBB+1 causes a dysfunctional UPS in these multifactorial neurodegenerative diseases. Novel transgenic mouse models and large-scale expression profiling and functional analyses of enzymes of the UPS compounds – enabling us to identify the targets of the UPS in these conformational diseases – may now pave the way for intervention and treatment of AD. Show more

Keywords: Conformational diseases, molecular misreading, polyglutamine diseases, synucleinopathies, tauopathies, vasopressin

DOI: 10.3233/JAD-2006-9S336

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 319-325, 2006

Authors: Levy, Efrat | Prelli, Frances | Frangione, Blas

Article Type: Research Article

Abstract: Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is similar to the 40–42 residues amyloid β (Aβ) in vessel walls and senile plaques in brains of patients with Alzheimer's disease (AD), Down's syndrome, and familial and sporadic cerebral amyloid angiopathy (CAA). In 1990 we sequenced the amyloid β-protein precursor (AβPP) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution, Aβ E22Q. Subsequent identification of additional mutations in the AβPP gene in familial AD (FAD) pedigrees revealed that whereas substitutions in the …middle of Aβ, residues Aβ21-23, are predominantly vasculotropic, those found amino- or carboxyl-terminal to the Aβ sequence within AβPP enhance amyloid parenchymal plaque deposition. Studies of transfected cells showed that substitutions amino- or carboxyl-terminal to Aβ lead to either greater Aβ production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Aβ1-42. Substitutions in the center of Aβ facilitate rapid aggregation and fibrillization, slower clearance across the blood-brain barrier and perivascular drainage to the systemic circulation, possibly higher resistance to proteolysis, and enhanced toxicity towards endothelial and smooth muscle cells. However, most AD patients have no genetic defects in AβPP, indicating that other factors may alter Aβ production, conformation, and/or clearance initiating the disease process. Show more

Keywords: Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), cerebral amyloid angiopathy (CAA), amyloid β-protein precursor (AβPP), amyloid β (Aβ)

DOI: 10.3233/JAD-2006-9S337

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 329-339, 2006

Authors: Goate, Alison

Article Type: Research Article

Abstract: In 1991 we described a missense mutation in the amyloid β-protein precursor (AβPP) gene in two familial Alzheimer's disease (FAD) kindreds. This gene encodes the amyloid β peptide deposited in senile plaques in AD. We made four predictions based upon these results: 1. Other FAD kindreds would be identified wth AβPP mutations; 2. FAD is genetically heterogeneous; 3. Aβ deposition is central to the pathogenesis of AD and 4, Regulatory variants in the AβPP gene lead to late onset AD. In the ensuing years substantial evidence has accrued in support of these predictions. Nineteen mutations in the AβPP gene have …been reported. These mutations have all been shown to alter AβPP processing or Aβ fibrillogenesis, leading to early Aβ deposition. Furthermore, mutations in the genes encoding presenilin 1 and presenilin 2, that cause FAD, also lead to changes in AβPP processing and Aβ deposition. Together these observations strongly support the hypothesis that Aβ deposition is central to AD pathogenesis. Suprisingly, the fourth prediction, that variation in AβPP expression may predispose to late onset AD, has not been rigorously tested, despite the fact that overexpression of AβPP is sufficient to cause dementia and AD neuropathology in Down Syndrome. Show more

Keywords: Familial Alzheimer's disease, Amyloid β-protein precursor, Amyloid β, gene, mutation, pathogenesis

DOI: 10.3233/JAD-2006-9S338

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 341-347, 2006

Authors: Goldgaber, Dmitry

Article Type: Research Article

Abstract: When I decided to clone the amyloid gene I did not know that there were some twenty groups around the research world that desperately tried to do the same. If I knew that I would have never started the project. I was so ignorant about the disease that I did not know how to spell the name Alzheimer. I had to look at the papers of other researchers to make sure that my spelling was correct. After the cloning, I was invited to numerous national and international meetings on AD. These meetings became my University where I majored in AD.

DOI: 10.3233/JAD-2006-9S339

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 349-360, 2006

Authors: Roses, Allen D.

Article Type: Research Article

Abstract: The association of Apolipoprotein E-4 with the age of onset of common late-onset Alzheimer's disease (AD) was originally reported in three 1993 papers from the Duke ADRC (Alzheimer's Disease Research Center) group [1--3]. The Center was investigating two diverse experimental streams that led to this discovery. The first being a genetic linkage study performed in multiplex familial late-onset AD in which a linkage was discovered at chromosome 19q13 [4,5]. The 1991 multilocus analysis of linkage had been considered very controversial [6]. The second stream came from a series of amyloid-β binding studies in which a consistent protein “impurity” was present …on gel separation analyses [1]. After sequencing this “impurity” band, several tryptic peptide sequences were found to be identical for apoE which, at that time, had no known association with Alzheimer's disease. The flash of recognition was the knowledge that APOE was one of the first genes localized to chromosome 19 in the mid-1980's. Within a three week period in late 1992, a highly significant association was identified in clinical patients from multiplex families, in sporadic clinical patients, and in autopsy diagnosed series [1,2]. Within the first two months of 1993, it was possible to clearly demonstrate that the APOE isoforms were associated with differing ages of onset, but the course of illness following diagnosis was related more to age than APOE genotype [3]. The earliest submitted paper reported the familial association and amyloid-β binding [1]. The second reported the association with common sporadic late-onset, [not-known to be familial] AD patients [2]. The third reported that APOE4 carriers had earlier rates of onset of clinical disease than APOE2 or APOE3 carriers [3]. Subsequently, over more than a decade, the biological expression of apoE in human neurons was confirmed as distinct from rodent brain [7,8] Proteomic experiments and positron emission tomography data have led to a series of clinical trials with agents selected to increase glucose utilization. These agents also regulate inflammatory responses of neural cells. Rosiglitazone, a PPARγ agonist which also leads to mitochondrial proliferation shown efficacy as a monotherapy in a Phase IIB clinical trial of 511 patients in an APOE allele-specific analysis. Show more

DOI: 10.3233/JAD-2006-9S340

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 361-366, 2006

Authors: Schellenberg, Gerard D.

Article Type: Research Article

Abstract: The genetics community working on Alzheimer's disease and related dementias has made remarkable progress in the past 20 years. The cumulative efforts by multiple groups have lead to the identification of three autosomal dominant genes for early onset AD. These are the amyloid-β protein precursor gene (APP), and the genes encoding presenilin1 and 2. The knowledge derived from this work has firmly established Aβ as a critical disease molecule and lead to candidate drugs currently in treatment trials. Work on a related disease, frontotemporal dementia with parkinsonism – chromosome 17 type has also added to our understanding of pathogenesis by …revealing that tau, the protein component of neurofibrillary tangles, is also a critical molecule in neurodegeneration. Lessons learned that still influence work on human genetics include the need to recognize and deal with genetic heterogeneity, a feature common to many genetic disorders. Genetic heterogeneity, if recognized, can be source of information. Another critical lesson is that clinical, molecular, and statistical scientists need to work closely on disease projects to succeed in solving the complex problems of common genetic disorders. Show more

Keywords: Alzheimer disease, AβPP, genetics, mutation, tau

DOI: 10.3233/JAD-2006-9S341

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 367-372, 2006

Authors: Spillantini, Maria Grazia | Murrell, Jill R. | Goedert, Michel | Farlow, Martin | Klug, Aaron | Ghetti, Bernardino

Article Type: Research Article

Abstract: Work in 1980s and early 1990s established that the microtubule-associated protein tau is the major component of the paired helical filament of Alzheimer's disease. Similar filamentous deposits are also present in a number of other diseases, including progressive supranuclear palsy, corticobasal degeneration and Pick's disease. In 1998, the relevance of tau dysfunction for the neurodegenerative process became clear, when mutations in the tau gene were found to cause the inherited “frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)”. The paper highlighted here [Spillantini M.G., Murrell J.R., Goedert M., Farlow M., Klug A. and Ghetti B. (1998) Mutation in the …tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737–7741] reported a mutation at position + 3 in the intron following alternatively spliced exon 10 of the tau gene in a family with abundant filamentous deposits made exclusively of four-repeat tau. Levels of soluble four-repeat tau were increased in individuals with this mutation. It was proposed that the + 3 mutation destabilises a stem-loop structure located at the end of exon 10 and the beginning of the intron, thus resulting in an abnormal ratio of three-repeat to four-repeat tau isoforms. Show more

Keywords: Mutation, tau, tauopathy

DOI: 10.3233/JAD-2006-9S342

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 373-380, 2006

Authors: Rogaeva, Ekaterina | Kawarai, Toshitaka | George-Hyslop, Peter St

Article Type: Research Article

Abstract: About 1% of Alzheimer's Disease (AD) cases have an early-onset autosomal dominant familial form of the disease, genetic analyses of which have found three causal genes: amyloid β-protein precursor (AβPP), presenilin 1 (PS1) and presenilin 2 (PS2). The APOE gene is the only robustly replicated risk factor for the common form of AD with onset after 65 years of age. In at least half of the AD cases, there is no known cause of the disease. Here we provide an overview on known AD-linked genes and discuss the strategies of searching for novel AD genetic risk factors.

Keywords: Alzheimer's disease, presenilin, gene, AβPP, APOE

DOI: 10.3233/JAD-2006-9S343

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 381-387, 2006

Authors: Van Broeckhoven, Christine | Kumar-Singh, Samir

Article Type: Research Article

Abstract: Development of therapeutics begins with delineating the precise disease pathology along with a reasonable understanding of the sequence of events responsible for the development of disease, or disease pathogenesis. For Alzheimer's disease (AD), the classical pathology is now known for quite some time; however, the disease pathogenesis has eluded our understanding for a complete century. This review, in addition to providing a brief overview of all primary events, will highlight those aspects of AD genetics and novel pathological descriptions linked to unique mutations within AβPP that have led to our better understanding of the pathogenesis of AD. Specifically, we will …discuss how pathologies linked to the Dutch (E693Q) and Flemish AβPP (A692G) mutations have helped in understanding the role of CAA in dementia and in the development of dense-core plaques. In addition, this review will also point directions that warrant additional studies. Show more

Keywords: Dementia, Alzheimer's disease, Cerebral Amyloid Angiopathy (CAA), cerebral hemorrhages, AβPP mutations, Flemish APP692 disease, HCHWAD

DOI: 10.3233/JAD-2006-9S344

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 389-398, 2006

Authors: Skoch, Jesse | Hyman, Bradley T. | Bacskai, Brian J.

Article Type: Research Article

Abstract: Multiphoton microscopy is an optical imaging technique that allows high resolution detection of fluorescence in thick, scattering tissues. The technique has been used for trans-cranial imaging of the brains of living transgenic mouse models of Alzheimer's disease. Direct detection of senile plaques in these mice has allowed the characterization of the natural history of individual senile plaques, the evaluation of plaque clearance during immunotherapy, and the characterization of the kinetics and biodistribution of the PET ligand, PIB. With the expanding repertoire of structural and functional fluorescent probes, and the preclinical characterization of new contrast agents for complementary imaging modalities like …MRI, PET, SPECT, and NIRS, multiphoton microscopy will continue to be a powerful tool in understanding and combating Alzheimer's disease. Show more

DOI: 10.3233/JAD-2006-9S345

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 401-407, 2006

Authors: Khachaturian, Zaven S.

Article Type: Research Article

Abstract: A retrospective view of the critical events and advances in the development of criteria, instruments and algorithms in the diagnosis of Alzheimer's disease. The review is from the vantage point of the National Institute on Aging and its role in the development of the national infrastructure, in the US, for clinical research on dementia. The paper discusses future research needs and challenges for developing new diagnostic armamentarium for early and accurate detection of neurodegenerative processes of dementia in the early prodromal stages or during early mild cognitive impairments.

Keywords: Diagnosis, dementia, Alzheimer's disease, mild cognitive impairments, MCI, diagnostic criteria, biomarkers, diagnostic instruments, neuroimaging, National Institute on Aging, NIA, NIH

DOI: 10.3233/JAD-2006-9S346

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 409-415, 2006

Authors: McKeith, Ian G.

Article Type: Research Article

Abstract: Dementia with Lewy bodies (DLB) was considered to be an uncommon cause of dementia until improved neuropathological staining methods for ubiquitin were developed in the late 1980's. Subsequent recognition that 10–15% of dementia cases in older people were associated with Lewy body pathology led to the publication in 1996 of Consensus clinical and pathological diagnostic criteria for the disorder. These have greatly raised global awareness of DLB and helped to generate a body of knowledge which informs modern clinical management of this pharmacologically sensitive group of patients. They have also enabled important issues surrounding the relationships of DLB with Alzheimer's …disease and Parkinson's disease to be addressed and partially resolved. A recent re-evaluation of the Consensus criteria has confirmed many aspects of the original recommendations, supplementing these with suggestions for improved pathological characterisation, clinical detection and management. Virtu-ally unrecognised 20 years ago, DLB could within this decade be one of the best characterised and potentially treatable neurodegenerative disorders of late life. Show more

Keywords: Dementia with Lewy bodies, diagnosis

DOI: 10.3233/JAD-2006-9S347

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 417-423, 2006

Authors: Morgan, Dave

Article Type: Research Article

Abstract: A primary goal of research on Alzheimer's disease is to develop disease modifying therapeutics. The amyloid cascade hypothesis has focused the initial efforts on methods to reduce amyloid. One surprising approach that has shown considerable success in mouse models and has hinted at benefits in human trials is anti-Aβ immunotherapy. Schenk first showed the amyloid reducing potential of active immunization in 1999. This prompted our group and that of St. George-Hyslop to investigate whether active immunization would similarly retard the memory deficits that develop in amyloid depositing transgenic mice. Contrary to our initial predictions of premature memory dysfunction due to …inflammation, vaccination protected amyloid depositing mice from developing memory deficits. Subsequent studies found that passive immunization could reverse memory deficits, even when administered for short periods. These encouraging findings led to a trial of an Aβ vaccination in Alzheimer patients. The trial was cut short due to meningoencephalitic symptoms in 6% of patients, yet, in a subset of patients, those developing brain reactive antibodies benefited from slower rates of cognitive decline. These observations have accelerated the development of passive immunization protocols and safer vaccines. At this time, anti-amyloid immunotherapy stands poised to be the first test of the amyloid hypothesis in the treatment of Alzheimer disease. Show more

Keywords: Alzheimer disease, amyloid-β, therapeutics, transgenic, vaccine

DOI: 10.3233/JAD-2006-9S348

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 425-432, 2006

Authors: Solomon, Beka

Article Type: Research Article

Abstract: Site-directed antibodies which modulate conformation of amyloid-β peptide (Aβ) became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3–6 of the N-terminal region of Aβ, found to be a key position in modulation of Aβ conformation, prevent formation of fibrillar Aβ and dissolve already formed amyloid plaques. The performance of anti-Aβ antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and/or dissolving Aβ. Moreover, these antibodies protected the mice from learning and age-related memory …deficits. Development of such antibodies via active and/or passive immunization against Aβ peptide fragments has been proposed for AD immunotherapeutic strategies. Experimental active immunization with fibrillar Aβ 1-42 in hu-mans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. In spite of the fact that it will take considerable effort to establish a suitable immunization procedure, these results clearly strengthen the hypothesis that Aβ plays a central role in AD, stimulating a new area for development of Alzheimer's immunotherapeutics. Show more

Keywords: Amyloid-β, site-directed antibodies, therapeutic chaperones, single-chain antibodies, EFRH sequence, immunomodulation

DOI: 10.3233/JAD-2006-9S349

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 433-438, 2006

Authors: Summers, William K.

Article Type: Research Article

Abstract: The story of the development of tacrine began from its synthesis as an intravenous antiseptic in 1940 by Adrian Albert in Australia. In the 1970's William Summers began using tacrine in treating drug overdose coma and delirium. He felt it might have application in Alzheimer's based on work done in England by Peter Davies. In 1981, Summers et al. gave intravenous tacrine to Alzheimer's patients showed measurable improvement. Between 1981 and 1986, Summers worked with Art Kling and his group at UCLA to demonstrate usefulness of oral tacrine in treatment of Alzheimer's patients. The average length of tacrine use in …14 completing patients was 12.6 months and improvement was robust. This sparked controversy in the field. In 1993, after larger studies replicated the positive effect of tacrine, it was approved by the US Food and Drug Administration for treatment of Alzheimer's disease. Show more

DOI: 10.3233/JAD-2006-9S350

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 439-445, 2006

Authors: Whitehouse, Peter J.

Article Type: Research Article

Abstract: Our paper on loss of neurons in the Nucleus Basalis of Meynert (now considered part of the cholinergic basal forebrain) in Alzheimer disease (AD) stimulated scientific interest in this little studied brain region. Our subsequent studies associated pathology in the basal forebrain with other dementias, such as Parkinson's disease, and with neurotransmitter receptor changes, such as in nicotinic receptors. We and many others worked to develop medications to treat AD through cholinergic mechanisms and eventually four cholinesterase inhibitors were approved. However the effect sizes of currently available drugs are modest and ethical issues in conducting research in dementia are challenging. …In Cleveland we came to focus on the goals of improving quality of life and the importance on non-pharmacological approaches to treatment. International efforts were organized to improve the efficiency of drug development and to focus on important cultural and pharmacoeconomic issues. Eventually I became concerned about the very way we conceive AD and related concepts like MCI (mild cognitive impairment). As the hundredth anniversary of the first case approaches I am helping to organize meetings to reflect deeply on what we have learned and how to imagine creating a more positive future for persons affected by what I used to call AD. Show more

Keywords: Cholinergic basal forebrain, Alzheimer disease, neuropathology, drug development, quality of life, bioethics, cognitive science

DOI: 10.3233/JAD-2006-9S351

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 447-453, 2006