Okadaic acid increases autophagosomes in rat neurons: implications for Alzheimer's disease.
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.
Yoon
Seung Yong
SY
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, SongPa-Gu, Seoul, Korea.
Choi
Jung Eun
JE
Kweon
Hee-Seok
HS
Choe
Han
H
Kim
Seong Who
SW
Hwang
Onyou
O
Lee
Heuiran
H
Lee
Joo-Yong
JY
Kim
Dong Hou
DH
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
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