Induction of amyloid precursor protein by the neurotoxic peptide, amyloid-beta 25-35, causes retinal ganglion cell death.
Patients with Alzheimer's disease (AD) show a significantly increased incidence of glaucoma. AD is also associated with the occurrence of the neurotoxic peptide amyloid beta (Abeta). Therefore, we investigated whether Abeta is associated with retinal cell death in a retinal ganglion cell line (RGC-5). Treatment with Abeta(25-35), a neurotoxic fragment of Abeta, induced cell death in RGC-5 in both a concentration- and time-dependent manner. The amount of amyloid precursor protein was increased by treatment of RGC-5 and primary culture of mouse cortical neurons with fibril Abeta(25-35) and Abeta(1-42), which is a putative physiological neurotoxic fragment of Abeta present in AD. Amyloid precursor protein knockdown inhibited the cell death induced by Abeta(25-35). Treatment with Abeta(25-35) increased the amount of intracellular Abeta(1-40) and Abeta(1-42), while beta- and gamma-secretase inhibitors reduced cell death. Thus, the regulation of Abeta can be viewed as a new therapeutic target for glaucoma, especially in patients with coincident AD.
Tsuruma
Kazuhiro
K
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
Tanaka
Yuka
Y
Shimazawa
Masamitsu
M
Hara
Hideaki
H
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology / Q000633:toxicity*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C074636:amyloid beta-protein (25-35); D048049:Extracellular Signal-Regulated MAP Kinases