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A second cytotoxic proteolytic peptide derived from amyloid β-protein precursor

Abstract

The amyloid β-protein precursor gives rise to the amyloid β-protein, the principal constituent of senile plaques and a cytotoxic fragment involved in the pathogenesis of Alzheimer disease. Here we show that amyloid β-protein precursor was proteolytically cleaved by caspases in the C terminus to generate a second unrelated peptide, called C31. The resultant C31 peptide was a potent inducer of apoptosis. Both caspase-cleaved amyloid β-protein precursor and activated caspase-9 were present in brains of Alzheimer disease patients but not in control brains. These findings indicate the possibility that caspase cleavage of amyloid β-protein precursor with the generation of C31 may be involved in the neuronal death associated with Alzheimer disease.

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Figure 1: APP interaction with and cleavage by caspases in cultured cells.
Figure 2: Cell death and viability assay in cultured cells expressing various APP and CTF constructs.
Figure 3: C31 toxicity and expression by immunocytochemistry.
Figure 4: Caspase-8 and caspase-9 immunoreactivity in mouse brain.
Figure 5: In vivo caspase cleavage of APP in AD and control brains.
Figure 6: In vivo caspase-9 activation in AD and control brains.

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Acknowledgements

We thank the National Institute on Aging (AG12282 to D.E.B. and AG05131 to E.H.K.); the National Institute of Neurological Disorders and Stroke (NS37776 and NS35155 to D.E.B., and NS28121 to E.H.K.); The Alzheimer's Association (Zenith Award to E.H.K.); and X. Chen, R. Andrusiak and A. Peel for technical assistance. We also thank J. Toncoso and D. Price of Johns Hopkins University for access to the brain tissue. D.C.L. is an MD/PhD candidate in the National Institutes of Health Medical Scientist Training Program at University of California, San Diego (National Institutes of Health/National Institute of General Medical Sciences Training Grant PHSGM07198) and is the recipient of a grant from the Paul and Daisy Soros Fellowships for New Americans; the program is not responsible for the views expressed. S.R. is a National Science Foundation Predoctoral Fellow.

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Correspondence to Edward H. Koo or Dale E. Bredesen.

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Lu, D., Rabizadeh, S., Chandra, S. et al. A second cytotoxic proteolytic peptide derived from amyloid β-protein precursor. Nat Med 6, 397–404 (2000). https://doi.org/10.1038/74656

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