Locus coeruleus degeneration impairs forebrain arteriole physiology and perfusion in a rat model of Alzheimer's disease.

The locus coeruleus (LC) provides forebrain norepinephrine (NE) and degenerates early in Alzheimer's disease (AD). We have shown that experimental LC lesions in the Tg344-19 AD rat model result in parenchymal arteriole (PA) stenosis, blood-brain barrier permeability, amyloid angiopathy, and cognitive impairment. Here, we show that PAs from LC-lesioned Tg344-19 AD rats displayed increased myogenic tone and decreased responsiveness to TRPV4 channel agonists, which was reversible by NE replacement. MRI studies indicated reduced forebrain perfusion and fractional anisotropy in LC-lesioned animals compared to controls. Targeting LC-mediated effects on cerebral hemodynamics presents a compelling AD therapeutic target.