In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 23, No. 13 ( 2003-07-02), p. 5531-5535
Abstract:
The amyloid β peptide (Aβ) is a product of the sequential γ- and β-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 Aβ 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 Aβ 1–40 prevented the toxicity of secretase inhibitors in neuronal cells. Aβ 1–40 was protective in a concentration-dependent manner, and its effects were significant at concentrations as low at 10 p m . Importantly, the protective effects of Aβ were Aβ size-form specific, with the Aβ 1–42 size form affording limited protection and the Aβ 25–35 size form having very little protective effect. The present study demonstrates that inhibition of β-or γ-secretase activity induces death in neuronal cells. Importantly, this toxicity, which our data suggest is a consequence of a decline in neuronal Aβ levels, was absent in non-neuronal cells. This study further supports a key physiological role for the enigmatic Aβ peptide.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.23-13-05531.2003
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2003
detail.hit.zdb_id:
1475274-8
SSG:
12
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