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