The role of ADAM17 in cerebrovascular and cognitive function in the APP/PS1 mouse model of Alzheimer’s disease

• DOI: 10.3389/fnmol.2023.1125932
• Publication Date: 2023-03-02T06:16:05Z
• Authors: Yanna Tian; Katie Anne Fopiano; Vadym Buncha; Liwei Lang; Hayden A. Suggs; Rongrong Wang; R. Daniel Rudic; Jessica A. Filosa; Zsolt Bagi
• Keywords: Cognitive Decline

Introduction The disintegrin and metalloproteinase 17 (ADAM17) exhibits α-secretase activity, whereby it can prevent the production of neurotoxic amyloid precursor protein-α (APP). ADAM17 is abundantly expressed in vascular endothelial cells may act to regulate homeostatic responses, including vasomotor function, wall morphology, formation new blood vessels. role neurodegenerative diseases remains poorly understood. Here, we hypothesized that cerebrovascular plays a pathogenesis Alzheimer’s disease (AD). Methods results We found 9-10 months old APP/PS1 mice with b-amyloid accumulation short-term memory cognitive deficits display markedly reduced expression cerebral microvessels. Systemic delivery adeno-associated virus (AAV)-mediated re-expression improved functioning, without affecting plaque density. In isolated pressurized arteries endothelium-dependent dilation acetylcholine was significantly reduced, whereas smooth muscle-dependent nitric oxide donor, sodium nitroprusside maintained when compared WT mice. impaired vasodilation restored normal level by re-expression. artery biomechanical properties (wall stress elasticity) microvascular network density not affected Additionally, proteomic analysis identified several differentially molecules involved AD neurodegeneration neuronal repair mechanisms were reversed Discussion Thus, propose microvessels impairs vasodilator which contribute development dysfunction mice, potentially be targeted for therapeutic intervention AD.