Abstract

A growing body of evidence indicates that decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms accelerate the progression of neurodegenerative diseases such as vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias (ADRD). There is an urgent clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated Angiotensin-(1-7) peptide, PNA5, as a therapy to treat VCID and investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration as compared to the native Angiotensin-(1-7) peptide. Moreover, following treatment with 1.0/mg/kg subcutaneously for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of MasR results in a dose-dependent inhibition of ROS in human endothelial cells. Lastly, PNA5 treatment decreased VCID/HF induced activation of brain microglia/macrophages and inhibited circulating TNF-α, IL-7 and G-CSF serum levels while increasing the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammatory related brain diseases.