Cerebrovascular protective functions of amyloid precursor protein: Progress and therapeutic prospects

Under physiological conditions, amyloid precursor protein (APP) is critically important for normal brain development, neurogenesis, neuronal survival, and synaptic signaling. Dyshomeostasis of APP increases deposition and accumulation of amyloid β (Aβ) in the brain parenchyma and cerebral blood vessels thereby leading to development of Alzheimer's disease and cerebral amyloid angiopathy. In this review, we critically examine existing literature supporting the concept that endothelial APP performs important vascular protective functions in the brain. Studies in cultured human brain microvascular endothelium and cerebral arteries derived from genetically modified mice indicate that loss of APP impairs expression and function of Krüppel-like Factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS) thereby causing endothelial dysfunction. Congruency between the findings obtained in murine and human cerebrovascular endothelium is consistent with strong evolutionary conservation of APP, and reinforces the concept that APP is an important vascular protective protein. Furthermore, we highlight vascular protective effects of APP during aging. We also address the roles of endothelial prostacyclin and nitric oxide in control of expression and proteolytic cleavage of APP. Finally, we outline potential translational opportunities emerging from recent advances in understanding of cerebrovascular function of APP. Several pharmacologically active domains of APP have been identified thus providing templates for creation of novel peptides with therapeutic properties.