Abstract 14: Glyburide Treatment Improves Aortic Arch Pulse Wave Velocity In A Murine Model Of Alzheimer’S Disease

Abstract

Brain hyperexcitability is a defining feature of AD, where aberrant neuronal activity may be both a cause and consequence of the pathology. Identifying novel targets to modulate cellular excitability is an important treatment strategy. We showed that inward rectifying, ATP-sensitive potassium (K ATP ) channels regulate excitability at the neurovascular unit to impact production and aggregation of amyloid-beta (Aβ), a hallmark of AD. Sulfonylureas such as glyburide (GLY) are antidiabetic medications that inhibit K ATP channels. We demonstrated that systemic treatment with GLY decreased Aβ production and plaque pathology by modulating vascular K ATP channel activity and neuronal excitability. Here, we investigated whether GLY alters cardiac function or pulse wave velocity (PWV) in APPswe, PSEN1dE9 (APP/PS1) mice, a model of Aβ overexpression.Female APP/PS1 mice at 8 months of age with established amyloid plaque pathology were treated for 1 month with GLY (subcutaneous, slow release 2.5mg pellet, ~30μg/GLY/day) or Placebo (n = 5, each group). After 1 month, transthoracic echocardiography was performed (Vevo 2100 LAZR, FUJIFILM/VisualSonics, Inc.; Toronto, Ca) with a 30 MHz linear array transducer. There were no differences in Placebo vs. GLY mice for heart rate, cardiac output, E/e’ ratio, ejection fraction, and fractional shortening. Arterial stiffness, measured as PWV in the aortic arch [Distance (D)/Time (T); D = mm from ascending to descending aorta and T = (R to ascending aorta foot) - (R to descending aorta foot) in ms], was lower in GLY treated mice (5 ± 1 vs. Placebo 9 ± 1 mm/ms; p < 0.04). Wild Type females at 9 months of age (n = 5) reveal similar cardiac function values as Placebo and GLY treated APP/PS1 mice, with a trend for lower PWV (6 ± 1 mm/ms) than the APP/PSI Placebo group. Thus, short-term treatment with GLY does not impact overall cardiac function. Moreover, improved vascular stiffness in GLY-treated APP/PS1 mice may contribute to improved neurovascular coupling independent of changes in Aβ aggregation, since arterial stiffness is associated with increased cerebrovascular pathology in clinical studies. SLM: Bright Focus Fdn, NIA K01AG050719, Donors Cure New Vision; SMD: T32AA007565; Hypertension & Vasc Res Ctr; NCATS UL1TR001420 (Vevo Core)