Abstract: The β-amyloid precursor protein (βAPP) is the source of the amyloid β-peptide that accumulates in the brain in Alzheimer's disease. A major processing pathway for βAPP involves an enzymatic cleavage within the amyloid β-peptide sequence that liberates secreted forms of βAPP (APPSs) into the extracellular milieu. We now report that postischemic administration of these APPSs intracerebroventricularly protects neurons in the CA1 region of rat hippocampus against ischemic injury. Treatment with APPS695 or APPS751 resulted in increased neuronal survival, and the surviving cells were functional as demonstrated by their ability to synthesize protein. These data provide direct evidence for a neuroprotective action of APPSs in vivo.