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

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