ADAM17 overexpression improves cerebrovascular vasoreactivity and cognitive function in the APP/PS1 mouse model of Alzheimer's disease

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 and may act to regulate vascular homeostatic responses, including vascular growth and vasomotor function. We hypothesized that cerebrovascular ADAM17 plays a role in the pathogenesis of Alzheimer’s disease (AD). Here we found that 8-10 months old APP/PS1 mice (expressing transgenes for APP Swedish mutation and PSEN1 with L166P mutation) with significant cognitive deficits display a markedly reduced expression of ADAM17 in cerebral microvessels. Systemic delivery and AAV-mediated re-expression of ADAM17 in APP/PS1 mice improved cognitive functioning, without affecting β-amyloid plaque density. Moreover, we found that the endothelium-dependent vasodilator function of isolated and pressurized cerebral arteries in APP/PS1 mice was impaired, which was restored to normal levels by the ADAM17 re-expression. The cerebral microvascular network density in the APP/PS1 mice before or after ADAM17 re-expression was not affected. In addition, proteomic analysis identified several differentially expressed molecules involved in AD neurodegeneration and repair that were reversed by ADAM17 re-expression. Thus, we propose that a reduced ADAM17 expression in cerebral microvessels impairs vasodilator function, whereby it contributes to the development of cognitive dysfunction in APP/PS1 mice, and that ADAM17 can potentially be targeted for therapeutic intervention in AD. T32HL155011; 20PRE35211126 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.