The production of amyloid beta peptide is a critical requirement for the viability of central neurons.
The amyloid beta peptide (Abeta) is a product of the sequential gamma- and beta-secretase cleavage of amyloid precursor protein. Inhibitors of secretase enzymes have been proposed as a potential therapeutic strategy in the treatment of Alzheimer's disease. Here, we investigate the effect of inhibiting these key enzymes on the viability of a range of cell types. Treatment of rat cortical neurons for 24 hr with secretase inhibitors or an antibody that binds Abeta resulted in a marked reduction in cell viability, as measured by MTT reduction. Incubation with secretase inhibitors caused similar effects on other neuronal cell types (rat cerebellar granule neurons and the human SH-SY5Y cell line). Interestingly, rat astrocytes and a number of non-neuronal cell lines investigated (HEK293, DDT1-FM2, and human teratorhabdoid tumor cells) were unaffected by incubation with secretase inhibitors. The coincubation of Abeta1-40 prevented the toxicity of secretase inhibitors in neuronal cells. Abeta1-40 was protective in a concentration-dependent manner, and its effects were significant at concentrations as low at 10 pm. Importantly, the protective effects of Abeta were Abeta size-form specific, with the Abeta1-42 size form affording limited protection and the Abeta25-35 size form having very little protective effect. The present study demonstrates that inhibition of beta-or gamma-secretase activity induces death in neuronal cells. Importantly, this toxicity, which our data suggest is a consequence of a decline in neuronal Abeta levels, was absent in non-neuronal cells. This study further supports a key physiological role for the enigmatic Abeta peptide.
Plant
Leigh D
LD
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Boyle
John P
JP
Smith
Ian F
IF
Peers
Chris
C
Pearson
Hugh A
HA
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006224:Cricetinae; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D019579:Neocortex / Q000166:cytology / Q000196:embryology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human