Functional Roles of Amyloid-β Protein Precursor and Amyloid-β Peptides: Evidence from Experimental Studies

Amyloid-beta (A beta) has remained a central feature in research into Alzheimer's disease (AD). Yet the function of the amyloid-beta protein precursor (A beta PP) 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 A beta PP and A beta PP-derived peptides. A beta PP knock-out mice exhibit severe metabolic abnormalities and behavioral deficits, indicating an important physiological function of A beta PP. Also, an increasing body of evidence suggests that while A beta is undoubtedly linked to neurodegeneration, the soluble amino-terminal fragment of A beta PP (sA beta PPa) has neuroprotective, neurotrophic, and cell adhesive functions. Moderate overexpression of human A beta PP in rodents does not produce apparent A beta 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 A beta pathology show impaired cognitive performance, increased vulnerability to brain ischemia and trauma, and less favorable functional outcome even before A beta deposition. A delicate balance in A beta PP processing seems to determine its functional consequences. Thus, it is tempting to speculate that promotion of a-secretase-mediated cleavage of A beta PP, which leads to increased sA beta PPa production, provides a novel therapeutic strategy in the treatment of AD and brain injury.