| Co-Investigator(Kenkyū-buntansha) |
IKEDA Masaki Gunma University, Graduate School of Medicine, Instructor, 大学院・医学研究系, 助手 (50222899)
ABE Koji Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (20212540)
SHOJI Mikio Okayama University, Graduate School of Medicine and Dentistry, Associated Professor, 大学院・医歯学総合研究科, 助教授 (60171021)
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| Research Abstract |
To assess whether lipoproteins are physiologically able to balance and modulate the sAβ homeostasis in vivo, soluble Aβ levels in lipoprotein-depleted plasma were measured as a function of age in normal controls, Alzheimer's disease (AD) patients, and Down's syndrome (DS) cases. The reshaping of sAβ homeostasis, in particular the sAβ42-lipoprotein interaction, takes place over normal-60s, whereas mild AD patients appear to have impaired this anti-amyloidogenic mechanism resulting in a significant increase of lipoprotein-free sAβ42. Similar loss of function takes place in Down's syndrome patients. Lipoprotein-free sAβ remains significantly elevated from the presymptomatic through the symptomatic stages of the disease, and declines with the progression of the AD-like pathology. The dissociation of sAβ from lipoprotein-particles also occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Aβ prior to its parenchymal deposition in AD brains would support the hypothe
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sis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of sAβ species and cerebral amyloidosis. These data was corroborated with the analysis of pooled CSF soluble Aβ in normal control individual and AD via size-exclusion chromatography and ELISA. Lipoprotein-free sAβ in CSF was significantly decreased in AD, indicating that brain to CSF clearance of Lipoprotein-free sAβ can be impaired in AD and its failure, a pathological step in AD pathology.
We also found that the administration of melatonin partially inhibited the expected time-dependent-elevation of Aβ-amyloidosis, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice model of AD. To clarify a potential physiological role of melatonin in AD pathogenesis, we have monitored the effect of this hormone on Aβ clearance in transgenic mice. It is relevant to note that melatonin has ability to upregulate Aβ clearance out of the brain. These results presented here suggest that melatonin can be explored as disease-modifying agents in AD. Less
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