Muscarinic activation attenuates abnormal processing of beta-amyloid precursor protein induced by cobalt chloride-mimetic hypoxia in retinal ganglion cells.
beta-Amyloid peptide (Abeta), the major pathological factor in Alzheimer's disease, has recently been reported to be implicated in the development of glaucoma. In this study, we explored the effect of muscarinic activation on abnormal processing of beta-amyloid precursor protein (APP) induced by a risk factor hypoxia in retinal ganglion cells. Hypoxia mimetic compound cobalt chloride could increase the generation of Abeta via up-regulating the expression of APP as well as the expression of beta-secretase and gamma-secretase, whereas muscarinic receptor agonist pilocarpine could significantly attenuate this abnormal pathway, thereby resulting in a decreased amyloidogenic cleavage of APP. This finding may provide an insight into better understanding of pathophysiology for the retinal neurodegenerative disease and searching for its new modifying approach.
Zhu
Xu
X
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhou
Wei
W
Cui
Yongyao
Y
Zhu
Liang
L
Li
Juan
J
Xia
Zheng
Z
Shao
Biyun
B
Wang
Hao
H
Chen
Hongzhuan
H
D051722:ADAM Proteins / Q000096:biosynthesis; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis; D003035:Cobalt / Q000633:toxicity; D005901:Glaucoma / Q000378:metabolism*; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D018721:Muscarinic Agonists; D012333:RNA, Messenger; D011976:Receptors, Muscarinic; D003035:Cobalt; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D051722:ADAM Proteins; C018021:cobaltous chloride