2006 Fiscal Year Final Research Report Summary
Accumulation of intraneuronal amyloid β and cell cycle dysregulation in the brains of Alzheimer's disease
| Project/Area Number |
17591193
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Asahikawa Medical College |
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Principal Investigator |
NUNOMURA Akihiko ASAHIKAWA MEDICAL COLLEGE, MEDICAL COURSE, ASSOCIATE PROFESSOR, 医学部, 助教授 (60241436)
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| Co-Investigator(Kenkyū-buntansha) |
CHIBA Shigeru ASAHIKAWA MEDICAL COLLEGE, MEDICAL COURSE, PROFESSOR, 医学部, 教授 (90171941)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Alzheimer's disease / amyloid-β / cell cycle / proliferating cell nuclear antigen / immunocytochemistry / transgenic mouse / c-Myc |
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| Research Abstract |
Recently, growing body of evidence suggests an initial role of intraneuronal amyloid-β (Aβ) accumulation in the pathological cascade of AD. On the other hand, cell cycle dysregulation, i.e., abnormal cell cycle re-entry (CCRE) has been reported in vulnerable neurons in Alzheimer disease (AD).
To elucidate a possible connection between intraneuronal amyloid-β (Aβ) accumulation and CCRE in the brains of AD, we used an in situ approach to identify intraneuronal Aβ and proliferating cell nuclear antigen (PCNA), a marker of CCRE, in the postmortem brains of AD. Immunocytochemically, positive reactions with intraneuronal Aβ and PCNA were observed in the same neuronal populations in the serial sections of the hippocampus and occipitotemporal gyrus of AD (n=10), while both of the immnoreactions were faint in the age-matched control brains (n=5).
To further investigate an involvement of CCRE in neurodegeneration accompanied by Aβ pathology, we have developed double transgenic (CaMKII-MYC) mouse model that expresses a powerful cell cycle inducer, human c-MYC, specifically in forebrain neurons by using the tetracycline-controlled transactivator system under the CaMKII promoter. After 4 or 8-week MYC induction, brain sections of MYC-On mice displayed robust expression of MYC and CCRE markers such as PCNA and incorporation of bromodeoxyuridine (BrdU) in the hippocampal neurons in comparison to the basal levels in MYC-Off mice. Of particular interest, in MYC-On mice, but not MYC-Off mice, intraneuronal Aβ immunoreaction was detected by C-terminal specific antibodies for Aβ1-42 in the hippocampal neurons predominantly in the CA1 region.
These results suggest that cell cycle dysregulation may be one of the basic mechanisms underlying the neurodegeneration in AD.
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