Available online 5 September 2025, 108921

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.

Alzheimer's disease

Endothelial cells

Nitric oxide

Prostacyclin

adenoassociated virus 9

a disintegrin and metalloproteinase domain-containing protein 10

Amyloid precursor protein intracellular C-terminal domain

anti-microbial peptide

Amyloid precursor protein

amyloid precursor-like protein 1

amyloid precursor-like protein 2

β-site amyloid precursor protein-cleaving enzyme 1

brain microvascular endothelial cells

cerebral amyloid angiopathy

cationic arginine-rich peptide

cyclic guanosine monophosphate

diethylamine diazeniumdiolate

endothelial nitric oxide synthase

γ-aminobutyric acid type B receptor subunit 1a

human umbilical vein endothelial cells

Krüppel-like Factor 2

Kunitz protease inhibitor

synthetic α-secretase

soluble amyloid precursor protein α

© 2025 The Authors. Published by Elsevier Inc.