Reduced microvascular expression of ADAM17 contributes to cognitive impairment in Alzheimer's disease model, APP/PS1 mice.

The disintegrin and metalloproteinase 17 (ADAM17), abundantly expressed in cerebrovascular endothelial cells, is one of the important α-secretases involved in the cleavage amyloid precursor protein-α (APP). We hypothesized that abnormal function of vascular ADAM17 contributes to the cognitive impairment in Alzheimer's disease (AD). We used 8-10 months old male and female wild type and APP/PS1 mice containing human transgenes for both APP bearing the Swedish mutation and PSEN1 containing an L166P mutation. We found that the ADAM17 expression in brain microvessels is significantly reduced in the APP/PS1 mice, compared to wild type controls. Using the Morris Water Maze (MWM) behavior test the APP/PS1 mice showed longer latency to reach the hidden platform during the learning phase and spent significantly less time in the target quadrant during the memory probe test. ADAM17 was then overexpressed in APP/PS1 mice via tail vein systemic delivery of ADAM17-AAV9. After 4 weeks, the ADAM17 overexpressed APP/PS1 mice spend less time to reach the platform and spend more time in the target quadrant during the MWM test compared to the control, eGFP overexpressed APP/PS1 mice. Thus, we propose that down-regulation of cerebrovascular ADAM17 contributes to the development of cognitive dysfunction in APP/PS1 mice, which can be improved by AAV9 delivery of ADAM17.