Importance of the caspase cleavage site in amyloid-β protein precursor

Abstract

Reports from multiple laboratories have now been published analyzing the critical nature of the caspase cleavage site of amyloid-β protein precursor (AβPP) for cell death induction, synaptic loss, hippocampal atrophy, long-term potentiation, memory loss, neophobia, and other aspects of the Alzheimer's phenotype. Here we review the results and implications of these studies for the understanding of Alzheimer's disease pathophysiology and the potential development of therapeutics that target this site in AβPP.

Fig. 1

Cleavage of AβPP at Asp664 occurs in the PDAPP model of Alzheimer’s disease, both in the hippocampus and in the cortex, as demonstrated by a neo-epitope antibody directed against the eight residues (P8-P1) preceding the caspase cleavage site of human AβPP. Note that this cleavage is prevented in the PDAPP-D664A mice. The minimal signal in the NTg controls may be due to cross-reaction with cleaved endogenous mouse AβPP.