Abstract
Decreased brain blood flow, increased inflammation, and increased reactive oxidative species (ROS) are correlated to accelerated progression of both vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease related dementia (ADRD). It has been previously demonstrated that VCID models with blood brain barrier dysfunction exhibit hippocampal neuronal loss and impaired cognitive function. Our novel synthetic glycosylated Angiotensin-(1-7) derivative (PNA5), has an enhanced half-life and is optimized for better blood-brain-barrier penetration. In our preclinical VCID model, PNA5 treatment inhibits brain ROS production, and reverses cognitive deficits. We hypothesized that 1) neuronal cell count in the CA1 region of the hippocampus will be decreased in our heart failure (HF) induced VCID mouse model and 2) PNA5 treatment will mitigate neuronal cell loss within the hippocampus and protect cognitive function. VCID was induced in adult male C57BL/6J mice (10-15/group), via HF. Control mice underwent sham surgery. Following 5 weeks post coronary ligation, mice were treated with either 1) saline or 2) 50 micrograms/kg/day PNA5, via daily subcutaneous injection for 21 days. Novel-object recognition was used to measure cognitive function and is represented as a DRatio. VCID-Saline mice displayed cognitive impairment (DRatio mean -0.02, SE + 0.07) compared to Control-Saline (DRatio 0.57 + 0.1). Cognitive function was rescued by PNA5 treatment (DRatio 50micrograms/kg/day 0.61 + 0.09). Hippocampal neuronal cell loss was determined through analysis of free-floating formalin fixed 16micron cryosection brains, stained with NeuN (ab177487, 1:500) and counted using ImageJ. CA1 Hippocampal regions (-1.6 to -2.0 millimeters from bregma) were imaged at 40x magnification. Data were analyzed by one-way ANOVA. VCID-Saline mice displayed a significant decrease in neurons in the CA1 region (3.35 + 0.11 cell/ pixel linear area) compared to Control-Saline mice (3.94 + 0.12). Mice treated with PNA5 had significantly higher CA1 neuronal cell count (3.87 + 0.17) in comparison to VCID-Saline treated mice. These data suggest that PNA5 protects against VCID cognitive impairment and prevents neuronal cell loss in VCID mouse models.
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