PNA5: A Novel Therapy for Heart Failure Induced Vascular Dementia

Abstract

Decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms contribute to cognitive impairment and neurodegenerative disease progress, including vascular contributions to cognitive impairment and dementia (VCID). However, the specific mechanisms that underlie heart failure (HF)-induced VCID are not clearly elucidated. Hence, in this work of experiments to identify biomarkers and test PNA5 treatment in HF-induced VCID, we also needed to establish the mechanisms for HF-induced VCID as a unique disease model that in itself is able to be identified and treated.This present study aims to 1) establish the pathophysiology associated with the progression/development of HF-induced VCID and establish biomarkers to predict HF individuals at risk for developing VCID and 2) advance our novel pluripotent peptide, PNA5. We hypothesize that 1) PNA5 will improve cognitive outcomes in HF-induced VCID via neuroprotective effects by decreasing neuronal damage, inflammation, blood-brain barrier (BBB) permeability, and neurovascular coupling (NVC) function, and 2) that NfL is a biomarker for cognitive impairment in HF individuals and that NfL will increase with increased cognitive impairment as HF severity progresses. To answer our hypothesis, we measured PNA5 neuroprotective effects in our HF-induced VCID mouse model. VCID was induced via myocardial infarction (MI). Mice were treated for 24 days with subcutaneous injections of PNA5 (500 mcg/kg/day or 50 mcg/kg/day) or saline (as control) five weeks after the MI. Cognitive function was assessed following the treatment protocol, and NVC was analyzed. NfL and cytokine levels were measured from blood collected at death. Brains were either homogenized to analyze brain cytokine levels or total hemisphere BBB permeability or sectioned and stained to analyze microglia morphology and regional BBB permeability. Biomarkers in the clinical studies, including NfL and pTau181, were measured from individuals (ages <50) with HF. HF individuals also underwent a battery of neuropsychological tests to assess cognitive performance. We observed that HF-induced VCID mice had increased intracerebral inflammatory responses, NVU dysregulation, and BBB leakage. PNA5 mitigated this mechanism and decreased markers for neuronal damage/death, thereby rescuing cognitive function independent of changes in heart function. These results are reflected in our clinical results, showing that NfL and pTau181 both negatively correlated to cognitive impairment and positively correlated to HF severity. Further, our results indicate that NfL may be a sensitive predictive biomarker for cognitive impairment in HF individuals and that PNA5 protects against cognitive impairment potentially through intervening in these neurotoxic mechanisms. Using an ischemic reperfusion injury mouse model, we also showed that PNA5 can improve heart function and decrease infarct size and fibrosis when treated immediately after reperfusion. These results indicate that PNA5 improves cognitive outcomes via neuroprotective effects on inflammation and vascular changes. Our work has further defined HF-induced VCID and made efforts to establish a biomarker panel to indicate disease progression.