title: Okadaic acid increases autophagosomes in rat neurons: implications for Alzheimer's disease.
abstract: Autophagosomes are accumulated in Alzheimer's disease (AD), but the regulatory pathway of autophagy in AD remains largely unknown. By using electron microscopy, Western blotting, and immunocytochemistry, here we show that autophagosomes are accumulated in rat neurons by okadaic acid (OA), a protein phosphatase-2A inhibitor known to enhance tau phosphorylation, beta-amyloid (Abeta) deposition, and neuronal death, which are the pathological hallmarks of AD. Autophagy can be generally induced via several distinct pathways, such as inhibition of mTOR or activation of beclin-1. Interestingly, OA increased both mTOR and beclin-1 pathways simultaneously, which suggests that autophagy in OA-treated neurons is induced mainly via the beclin-1 pathway, and less so via mTOR inhibition. Finally, inhibition of autophagy by 3MA reduced cytotoxicity in OA-treated neurons. Our novel findings provide new insights into the pathology of and therapeutic intervention for AD.
authors.affiliation: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, SongPa-Gu, Seoul, Korea.
authors.forename: Seung Yong
authors.initials: SY
authors.lastname: Yoon
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Choi
authors.forename: Hee-Seok
authors.initials: HS
authors.lastname: Kweon
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
authors.forename: Heuiran
authors.initials: H
authors.lastname: Lee
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Dong Hou
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007150:Immunohistochemistry; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019319:Okadaic Acid / Q000633:toxicity*; D010588:Phagosomes / Q000187:drug effects* / Q000648:ultrastructure; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019319:Okadaic Acid; C025946:3-methyladenine; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D000225:Adenine