共同企画
教育講演
タウオパチーの分子病態と病理 |
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| 7月7日（金） 10:40-12:40 Room A
2EL①-1
タウオパチーの画像診断
Diagnostic imaging of tauopathies
樋口 真人1,2
1. 量子科学技術研究開発機構, 2. 大阪公立大学
Makoto Higuchi1,2
1. National Institutes for Quantum Science and Technology, 2. Osaka Metropolitan University
Depositions of tau fibrils are neuropathological hallmarks of Alzheimer’s disease (AD) and related disorders. Visualization of tau pathologies by positron emission tomography (PET) accordingly facilitates the diagnosis and differentiation of diverse tauopathies. Several small-molecule PET probes were generated to capture AD-type tau fibrils and have been of utility for separating AD-spectrum patients from healthy controls. These radiochemicals have been applied to the stratification of subjects for reinforcing the therapeutic effects of anti-amyloid-beta antibodies and to the evaluation of antisense oligonucleotides against tau transcripts. Meanwhile, few probes were shown to be highly reactive with non-AD, primary tauopathies. We developed a PET ligand, PM-PBB3 (aka florzolotau), and have demonstrated the high performance of this compound in detecting tau deposits in progressive supranuclear palsy (PSP), corticobasal degeneration, and Pick’s disease. The presence of tau inclusions characteristic of these diseases was proven by autopsy and biopsy examinations of cases who had undergone a florzolotau-PET scan. Longitudinal PET studies have also shown that progressive tau accumulations in AD and PSP are trackable with florzolotau, indicating the potential utility of this probe for examining disease-modifying effects of anti-tau therapeutics in various tauopathies. | | 7月7日（金） 10:40-12:40 Room A
2EL①-2
Critical Involvement of Tau in Alzheimer’s Disease and Related Neurodegenerative Disorders
Iqbal Khalid
Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities
Tau is the major microtubule associated protein of the neuron which helps maintain the axoplasmic transport by maintaining the microtubule network in the cell. This activity of tau is regulated by its degree of phosphorylation which in turn is primarily regulated by protein phosphatase 2A. In Alzheimer’s disease (AD) and a family of related neurodegenerative diseases, called tauopathies tau is abnormally hyperphosphorylated. Unlike tau in normal human brain which contains 2-3 phosphate groups per molecule of the protein, in AD it is 3-4-fold hyperphosphorylated. While normal tau binds to the microtubule subunit protein, tubulin and promotes its assembly into microtubules, the AD hyperphosphorylated tau, instead, binds to normal tau and the tau-hyperphosphorylated tau becomes a substrate for hyperphosphorylation. This sets up a vicious cycle which results in the affected neuron to continue synthesizing tau to that lost by its sequestration by the hyperphosphorylated protein. The hyperphosphorylation makes tau resistant to proteolytic digestion and the affected neuron protects itself by polymerizing the hyperphosphorylated tau into bundles of paired helical filaments, called neurofibrillary tangles. The density of neurofibrillary tangle/ tau pathology directly correlates with the degree of dementia. The affected neuron loses its connectivity to other neurons both because of the compromised axonal transport due to reduction of functional tau and by disruption of the network caused by the space occupying of the cell cytoplasm by the tangle. Eventually neurons with tau pathology die and the hyperphosphorylated aggregated tau released in the extracellular space becomes seeds for further spread of the pathology. These studies have led to tau immunotherapy as one of the major therapeutic approaches for the treatment of AD. In our laboratory we have discovered that passive immunization with a mouse monoclonal antibody to amino terminal projection domain of tau, tau6-18 could not only clear tau but also Abeta pathology and rescue cognitive impairment in 3xTg-AD transgenic mouse model of AD. Furthermore, we found that tau immunotherapy could also inhibit the seeding and spread of AD hyperphosphorylated tau-induced tau pathology in mice. Thus, inhibition of tau pathology has the potential to lead to an effective disease modifying treatment for AD and related tauopathies. (Studies in our laboratory were supported in part by NIH/NIA grants and the New York State Office of People with Developmental Disabilities [OPWDD]). | | 7月7日（金） 10:40-12:40 Room A
2EL①-3
Neuropathology of tauopathies
吉田 眞理
愛知医科大学 加齢医科学研究所
Mari Yoshida
Depart. of Neuropathol., Institute for Med. Science of Aging, Aichi Med. Univ.,Nagakute, Japan
Tau is a microtubule associated protein (MAP) and implicates in microtubule initiation as well as assembly. Tauopathies are clinically, pathologically and biochemically heterogeneous neurodegenerative disorders characterized by the aggregation of abnormal tau protein in the brain. The neuropathological classification is based on the presence of distinct isoforms of tau in the pathological deposition, cell types, and involvement of various anatomical regions. It comprises Alzheimer’s disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), argyrophilic grain disease (AGD). AD reveals neurofibrillary tangles (NFT) composed of both three (3R) and four (4R) tau isoforms with deposition of amyloid-β. PiD is a prototype of FTLD. Neuronal cytoplasmic 3R-tau immunoreactive Pick bodies are characteristic features. PSP, CBD, GGT and AGD are 4R tauopathies. PSP and CBD have a wide clinicopathological spectrum. The microscopic diagnostic hallmarks are tufted astrocytes in PSP and astrocytic plaques in CBD. Tau pathology are also observed in many other diseases, such as in chronic traumatic encephalopathy, and subacute sclerosing panencephalitis. The neuropathology of tauopathies is essential and structure-based classification of tauopathies may contribute to elucidate pathogenesis. | | | |
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