Alzheimer's-Related Peptide Amyloid-β Plays a Conserved Role in Angiogenesis

Alzheimer's disease research has been at an impasse in recent years with lingering questions about the involvement of Amyloid-beta (A beta). Early versions of the amyloid hypothesis considered A beta something of an undesirable byproduct of APP processing that wreaks havoc on the human neocortex, yet evolutionary conservation - over three hundred million years - indicates this peptide plays an important biological role in survival and reproductive fitness. Here we describe how A beta regulates blood vessel branching in tissues as varied as human umbilical vein and zebrafish hindbrain. High physiological concentrations of A beta monomer induced angiogenesis by a conserved mechanism that blocks gamma-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize gamma-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-a-vis vascular changes that set the stage for ensuing neurodegeneration.