Amyloid-β (Aβ) has remained a central feature in research into Alzheimer's disease (AD). Yet the function of the amyloid-β protein precursor (AβPP) and its processing products in the central nervous system is controversial. This review examines experimental literature from cell cultures to transgenic AD and brain injury models with a special emphasis on the functional role of AβPP and AβPP-derived peptides. AβPP knock-out mice exhibit severe metabolic abnormalities and behavioral deficits, indicating an important physiological function of AβPP. Also, an increasing body of evidence suggests that while Aβ is undoubtedly linked to neurodegeneration, the soluble amino-terminal fragment of AβPP (sAβPPα) has neuroprotective, neurotrophic, and cell adhesive functions. Moderate overexpression of human AβPP in rodents does not produce apparent Aβ pathology and has no significant effect on cognitive or sensorimotor behavior and, surprisingly, may even provide histological neuroprotection against focal cerebral ischemia. In contrast, phenotypes with more severe Aβ pathology show impaired cognitive performance, increased vulnerability to brain ischemia and trauma, and less favorable functional outcome even before Aβ deposition. A delicate balance in AβPP processing seems to determine its functional consequences. Thus, it is tempting to speculate that promotion of α-secretase-mediated cleavage of AβPP, which leads to increased sAβPPα production, provides a novel therapeutic strategy in the treatment of AD and brain injury. © 2009 - IOS.