- 著者
-
シュウ ワッシ
- 出版者
- 日本生理学会
- 雑誌
- 日本生理学会大会発表要旨集
- 巻号頁・発行日
- vol.2006, pp.35, 2006
Alzheimer's disease (AD), the most common form of senile dementia, is characterized by excessive production and accumulation of neurotoxic β-amyloid (Aβ) peptides which are proteolytically derived from β-amyloid precursor protein (APP) via β- and γ-secretase cleavages. Experimental evidence from several groups including our own has demonstrated that the production of Aβ occurs largely in the trans-Golgi network (TGN) where APP molecules predominantly reside. Mutations in presenilins genes are associated with the majority of familial AD likely through a mechanism of increase Aβ42 production. Presenilins (PS, PS1 and PS2) along with their associated proteins including nicastrin (Nct), PEN2 and APH1 are essential for the γ-secretase activity. The precise functions of Nct, APH-1 and PEN-2 have not been fully elucidated. Recent studies including ours suggest that PEN-2 mediates endoproteolysis of PS1, while APH-1 and Nct play regulatory roles in maintaining the stability of PS1 and the complex. PS1 knockout mice exhibit pre-neonatal lethality and PS1 has also been shown to affect numerous physiological functions including calcium homeostasis, skeletal development, neurite outgrowth, apoptosis, synaptic plasticity, tumorigenesis. These data strongly indicate critical physiological roles of PS1 addition to its essential role in γ-secretase activity. We and others have reported that PS1 plays an important role in intracellular trafficking (especially from the TGN to the plasma membrane) of select membrane proteins including APP, PEN2 and nicastrin. The detailed cell biological mechanism for PS-mediated protein trafficking will be discussed. <b>[J Physiol Sci. 2006;56 Suppl:S35]</b>