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The Journal of Neuroscience, July 2, 2003, 23(13):5531-5535

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BRIEF COMMUNICATION
The Production of Amyloid Peptide Is a Critical Requirement for the Viability of Central Neurons

Leigh D. Plant,¹ John P. Boyle,² Ian F. Smith,² Chris Peers,² and Hugh A. Pearson¹

¹Schools of Biomedical Sciences and ²Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, United Kingdom

The amyloid peptide (A) is a product of the sequential - and -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 A 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 A_1–40 prevented the toxicity of secretase inhibitors in neuronal cells. A_1–40 was protective in a concentration-dependent manner, and its effects were significant at concentrations as low at 10 pM. Importantly, the protective effects of A were A size-form specific, with the A_1–42 size form affording limited protection and the A_25–35 size form having very little protective effect.

The present study demonstrates that inhibition of -or -secretase activity induces death in neuronal cells. Importantly, this toxicity, which our data suggest is a consequence of a decline in neuronal A levels, was absent in non-neuronal cells. This study further supports a key physiological role for the enigmatic A peptide.

Key words: Alzheimer's disease; amyloid; secretase; inhibitor; nerve; cell death; physiology

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Received Sep. 9, 2002; revised Apr. 30, 2003; accepted Mar. 7, 2003.

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