Alzheimer's Disease: A Century of Scientific and Clinical Research
A-F | G-H | I-L | M-Q | R-S | T-Z
Massimo Tabaton, Pierluigi Gambetti
Soluble amyloid-ß in the brain: The scarlet pimpernel
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 Aß (sAß). Unexpectedly, this work produced several novel findings. First, we observed that N-terminal truncated peptides are the major components of soluble and insoluble Aß in AD; secondly, that all sAß species belong to the 42 form and the sAß x-40 species is virtually absent in AD parenchyma; thirdly, that Aß 42 in the soluble form is non-detectable by immunoblots in plaque-free, normal brains. The later observation that sAß 42 species is present in amyloid ß protein precursor (AßPP) over-expressing brains of patients with Down syndrome in prenatal and early postnatal development argued that sAß is present in brain in abnormal conditions and that its appearance seeds Aß aggregation and accumulation. Although the sAß we described in intact brain tissue appeared to match the soluble Aß oligomers detected in cell media, which were subsequently shown to be the most toxic form of Aß, our research has been virtually ignored by the Alzheimer field. It continues nevertheless. Recently we demonstrated that the species of sAß 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 Aß species associated with normal brain aging. Furthermore, in familial AD, the composition of soluble Aß appears to dictate distinctive features of the disease phenotype introducing the notion of Aß strains, a concept well established in prion diseases.
Dora Games, Manuel Buttini, Dione Kobayashi, Dale Schenk, Peter Seubert
Mice as Models: Transgenic Approaches and Alzheimer's Disease
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 ß protein precursor (AßPP) 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.
Bernardino Ghetti
Neurodegeneration and Hereditary Dementias: 40 Years of Learning
Abstract: The invitation to participate in the commemorative issue celebrating the 100 th anniversary of Dr. Alois Alzheimer's report on the disease that would later bear his name has evoked memories of my early experiences in the study of dementia, my teachers, my role-models, my aspirations and my accomplishments. Early in my career, I was fascinated with the study of hereditary neurological disorders. The observation of families in which dementia was inherited in an autosomal dominant pattern excited my scientific curiosity. Three very different phenotypes in patients from three separate families have been the basis for novel scientific discovery, which has taken place over the past 30 years. This could not have taken place without the help of many generous patients and their families as well as wonderful colleagues for whom I am deeply grateful. Some of the original observations in these families have led to the discovery of genetic mutations in three genes that are among the most commonly affected in hereditary dementia. The work on these families has enriched the scientific community and our knowledge of dementing illnesses.
Alison Goate
Segregation of a missense mutation in the amyloid ß-protein precursor gene with familial Alzheimer's disease
Abstract: In 1991 we described a missense mutation in the amyloid ß-protein precursor (AßPP) gene in two familial Alzheimer's disease (FAD) kindreds. This gene encodes the amyloid ß peptide deposited in senile plaques in AD. We made four predictions based upon these results: 1. Other FAD kindreds would be identified wth AßPP mutations; 2. FAD is genetically heterogeneous; 3. Aß deposition is central to the pathogenesis of AD and 4, Regulatory variants in the AßPP gene lead to late onset AD. In the ensuing years substantial evidence has accrued in support of these predictions. Nineteen mutations in the AßPP gene have been reported. These mutations have all been shown to alter AßPP processing or Aß fibrillogenesis, leading to early Aß deposition. Furthermore, mutations in the genes encoding presenilin 1 and presenilin 2, that cause FAD, also lead to changes in AßPP processing and Aß deposition. Together these observations strongly support the hypothesis that Aß deposition is central to AD pathogenesis. Suprisingly, the fourth prediction, that variation in AßPP expression may predispose to late onset AD, has not been rigorously tested, despite the fact that overexpression of AßPP is sufficient to cause dementia and AD neuropathology in Down syndrome.
Michel Goedert, Aaron Klug, R. Anthony Crowther
Tau protein, the paired helical filament and Alzheimer's disease
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 sequence 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.
Dmitry Goldgaber
The discovery and mapping to chromosome 21 of the Alzheimer amyloid gene. My story.
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 I 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.
John Hardy
Alzheimer's disease: the amyloid cascade hypothesis. Science 286 (1992) 184-185: an update and reappraisal
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.
Asao Hirano, Maki Iida
Topographic study of Alzheimer’s neurofibrillary changes: a personal perspective
Abstract: Argentophilic neurofibrillary tangles were described in the cerebral cortex of Alzheimer’s disease and later in the pigmented neurons in the brain stem of postencephalitic parkinsonism. In 1961, wide distribution of Alzheimer’s neurofibrillary tangles in the central nervous system was observed in endemic fatal neurodegenerative diseases affecting the native Chamorro population on Guam: amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam. Abundant neurofibrillary tangles were found but no senile plaques. A topographic analysis of tangles in cases in Guam and at Montefiore were published in 1962. Thereafter, Alzheimer’s neurofibrillary changes were documented in various areas of the nervous system of many other diseases. This communication is a brief review of the topographic investigation of Alzheimer’s neurofibrillary changes. Occurrence of tangles in various conditions seems to indicate that various pathological agents can induce tangles. On the other hand, Alzheimer’s neurofibrillary tangles, in general, show a rather striking predilection to affect particular neurons in the involved regions.
Jesse Skoch, Bradley T. Hyman, Brian J. Bacskai
Preclinical characterization of amyloid imaging probes with multiphoton microscopy
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.