A-F | G-H | I-L | M-Q | R-S | T-Z
Karen H. Ashe
Molecular basis of memory loss in the Tg2576 mouse model of Alzheimer disease
Abstract: Understanding the pathophysiology and treatment of Alzheimer disease is vitally important because the disease is the most common cause of dementia in the world, the fastest growing disorder in the United States, and the third costliest illness in the United States, consuming over $100 billion per year. Alzheimer disease threatens to affect nearly 50% of all individuals alive in the United States today, unless interventions are discovered to prevent or treat the disease. Although memory loss is the cardinal symptom of Alzheimer 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 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 disease in mice and rats.
Jesús Avila
Tau protein, the main component of paired helical filaments
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. Here, we review our study demonstrating for the first time that tau can self-polymerize and, at that time, it suggested that tau was not only a component of Alzheimer paired helical filaments, but that it was the main component of paired helical filaments.
Melvyn J. Ball
The Essential Lesion of Alzheimer Disease: A Surprise in Retrospect
Abstract: In the absence of any naturally occurring animal model of Alzheimer's disease (AD), the British conviction in the 1970's that clinicopathological investigations of human cases offered the best approach to unraveling the pathogenesis of AD rapidly influenced clinical neuroscientists, neuropathologists and funding agencies in Canada and the U.S.A. But as with my confreres, years of our quantifying AD lesions in autopsy brains have yet to yield definitive conclusions about what is the most important neuronal abnormality. However, during my elusive search, evidence has been slowly gathered that reactivation of latent Herpes simplex virus, traveling from trigeminal ganglia into neighbouring mesial temporal cortex, might best explain the limbic predilection for and earliest site of neurofibrillary tangle formation. This maturing hypothesis may serendipitously prove to have been a more essential byproduct of generating the voluminous data than all the publications from our laboratory that reflected endless hours of quantitative morphometry.
Jesse F. Ballenger
Progress in the History of Alzheimer’s Disease: the Importance of Context
Abstract: The history of Alzheimer’s disease (AD) is typically formulated as the history of great doctors and scientists in the past making great discoveries that are in turn taken up by great doctors and scientists in the present – all sharing the aim of unraveling the mysteries of disease and discovering how it can be prevented or cured. While it can certainly be edifying to study the “great men” and how their contributions laid the foundation for current work, there are problems with this approach to history. First, it oversimplifies the actual historical development of science. Second, using history to legitimate the present can keep us from asking critical questions about the aims and limits of contemporary research. This chapter urges a broader view of the history of AD, one that recognizes that context is as important as the great doctors to the historical development of the concept of AD. Thought of this way, I argue that it is useful to divide of the history of AD into three periods. First there was the period in which Alzheimer and Kraepelin laid the clinical and pathological foundations of the disease concept. Then there is our own period, which began in the late 1970s and has emphasized the biological mechanisms of dementia. In between, there is the period – almost completely ignored in most histories of AD – that conceptualized dementia in psychodynamic terms. It is true that the psychodynamic model of dementia did not directly contribute to the concepts and theories that dominate AD research today. But it did change the context of aging and dementia in important ways, without which AD could not have emerged as a major disease worthy of a massive, publicly supported research initiative.
Heiko Braak, Udo Rüb, Christian Schultz, Kelly Del Tredici
Vulnerability of cortical neurons to Alzheimer's and Parkinson's diseases
Abstract: Alzheimer's disease (AD) and sporadic Parkinson's disease (PD) are the most frequently occurring degenerative illnesses of the human nervous system. Both involve multiple neuronal systems, but only a few types of nerve cells are prone to develop the disease-associated intraneuronal alterations. In AD affected neurons produce neurofibrillary tangles and neuropil threads, while in PD they develop Lewy bodies and Lewy neurites. In both illnesses select types of projection cells that generate long, unmyelinated or sparsely myelinated axons are particularly susceptible. This kind of selective vulnerability induces a distinctive lesional pattern which evolves slowly over time and remains remarkably consistent across cases. In the present review, lesions developing in the cerebral cortex are described against the backdrop of the internal organisation and interconnectivities linking involved cortical areas and subcortical nuclei. In AD, six and in PD, three stages can be distinguished, reflecting the predictable manner in which the proteinaceous intraneuronal inclusions spread through the cerebral cortex. In AD stages I-II and in PD stage 4, the pathological process makes inroads into the anteromedial temporal mesocortex, entorhinal allocortex, and Ammon's horn; thereafter, in AD stages III-IV and in PD stage 5, it proceeds into the adjoining high order association areas of the basal temporal neocortex. In AD stages V-VI and in PD stage 6, the devastation engulfs additional neocortical association areas including first order association areas and eventually extends into the primary areas of the neocortex. The gradually evolving lesional pattern in AD and PD mirrors the ground plan of the cerebral cortex. The highest densities of lesions occur in the anterior mesocortical transitional zone between allo- and neocortex. From there, the involvement diminishes by degrees and extends into both the hippocampal formation and the neocortex. The severity of the neocortical lesions decreases in inverse proportion to the trajectories of increasing cortical differentiation and hierarchical refinement.
Jean-Pierre Brion
Immunological demonstration of tau protein in neurofibrillary tangles of Alzheimer's disease
Abstract: Neurofibrillary tangles are one of the neuropathological hallmark of Alzheimer's disease, described early as part of the pathological criteria of the disease. Ultrastructural 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.
Peter Davies
A Long Trek Down The Pathways Of Cell Death In Alzheimer's Disease
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.
André Delacourte
The natural and molecular history of Alzheimer's disease
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.
Esiri MM, Chance SA
Vulnerability to Alzheimer's pathology in neocortex: the roles of plasticity and columnar organization
Abstract: Two principal findings in the Pearson et al. [Proc Natl Acad Sci USA, 82 (1985) 4531-4] paper are commented on here. The first is the regional selectivity within the cerebrum of neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) which targets association cortex as well as the primary olfactory cortex alone among regions of primary sensory cortex. The second finding is the clustering of NFT in columns of supra- and infra-granular neurons of association cortex. We review recent evidence confirming these findings and comment on their possible significance. We consider that the most attractive hypothesis to explain the vulnerability of the olfactory system and association cortex is the persistent neural plasticity of these regions. On this basis there would be no need to postulate a progressive spreading process. The columnar distribution of clustered NFT can be well understood in the context of recent concepts of columnar organization of the cerebral cortex. The original interpretation that this distribution of NFT reflects pathology in neurons subserving cortico-cortical and cortico-subcortical connections seems to us to have stood the test of time.
Efrat Levy, Frances Prelli, Blas Frangione
Studies on the first described Alzheimer's disease amyloid β mutant, the Dutch variant
Abstract: Amyloid protein deposited in cerebral vessel walls 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 or conformation, initiating the disease process.
