| Project/Area Number |
06670194
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Human pathology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
II Kunio University of Tokushima, School of Medicine Associate professor, 医学部, 助教授 (50035507)
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| Co-Investigator(Kenkyū-buntansha) |
ONO Kazuo University of Tokushima, School of Medicine Senior (part-time doctor)., 医学部・附属病院, 医員
TANAKA Keiji University of Tokushima, Institute for Enzyme Research, Associate professor., 酵素科学研究センター, 助教授 (10108871)
TOWATARI Takae University of Tokushima, Institute for Enzyme Research, Assistant., 酵素科学研究センター, 助手 (60108876)
KOMINAMI Eiki Juntendo University School of Medicine, Professor., 医学部, 教授 (10035496)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1995: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1994: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | Alzheimer's disease / aging / protease / inhibitor / ubiquitin / cell degeneation / immunohistochemistry |
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| Research Abstract |
Our recent immunohistochemical studies of cathepsins B (CB), H (CH) and L (CL) and cystatins alpha(Calpha) and beta (Cbeta) in the brains of nonfamilial Alzheimer's disease (AD) and the related disorders suggested that proteolytic dysfunction in nerve and glial cells plays an important role in formations of NFT and Ab (Virchow's) Arch A 423 : 185-194,1993). On the base of this study, we have examined immunohistochemical localizations of lysosomal and non-lysosomal proteases in the brain of AD and the related disorders and aging including animal experiments.
The summary of results obtained so far is as follows.
1. Immunohistochemical localizations of CB and cathepsin D (CD) in familial AD (FAD,5 autopsy cases) in Tokushima showed that CB was selectively increased in the dystrophic neurites of SP and at the site of NFTas observed in our above-mentioned studies of non-familial AD.However, CD was absent frequently at the site of NFT,suggesting their different role or different stage of invol
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vement in details in proteolysis relating the formations of NFT and Ab.
2. The origin and mechanism of formation of granulovacuolar bodies (GVB) have been remained obscure.. Detailed observation and analysis of immunoreactivities of CB and CD in many GVB in AD (12 cases) and the related disorders (11 cases) and normal controls (6 cases) suggested that GVB was originated from the lysosomes and lysosome-related structures and formed as a result of their degeneration. Biochemical evidence for the swelling of lysosomes and the lysosome-related structures was also introduced to explain the mechanism of forming this unique structure.
3. Immunohistochemical colocalization of proteasome (Ps, an unique non-lysosomal protease) with ubiquitin (Ub) in variou neurodegenerative disorders was investigated to know the significance of ubiquitination of various inclusions and abnormal structures and to examine whether Ps is involved in proteolysis of ubiquitinated proteins. Ps was colocalized with Ub in most SP and Lewy bodies but not in NFT,filamentous inclusion, and eosinophilic granules. The result suggested that Ps is involved in some ubiquitinated proteins but not in all and not always.
4. Changes of immunolocalizations of CB and CD with aging in human brains (6d.-84y, 32 cases). Immunolocalizations of CB and CD were abundant from the age of 7 to 60 but decreased variously after about 60 years of age, suggesting dysfunction of lysosomal proteolysis.
5. Immunolocalization of CB in the old (2 y.) rat (10, in total), and in old (1y. 7m.) mice (58, in total) untreated and pretreated with leupeptin or chloroquine. CB-immunorectivity was decreased variously in some old rats and old mice pretreated with leupeptine, suggesting dysfunction of lysosomal proteolysis, but uncertain in mice pretreated with chloroquine. Less
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