Abstract Body: Arterial stiffening is associated with cognitive deficits and biomarkers of neurodegeneration; however, the mechanisms underlying this effect remain unexplored. We hypothesize that arterial stiffening induces neuroinflammation and reduces cerebral blood flow (CBF), contributing to cognitive impairment. To test this hypothesis, we induced a brief episode of hypertension by a two-week s.c. infusion of angiotensin II (Ang II; 600ng/kg/min) via osmotic mini pumps in 3-month-old male C57BL/6 mice. Blood pressure was measured twice per week by tail-cuff plethysmography. Systolic blood pressure increased during the Ang II infusion (Ang II: 141.8 vs saline: 110.7 mmHg; n=10 mice/group; p<0.0001) and returned to normal after pump removal on day 14 of infusion (124.8 ± 4.367 mmHg). Previous studies have established extensive aortic stiffening develops in the months following Ang II infusion. To test if arterial stiffening leads to cognitive impairment, we utilized a battery of neurobehavioral assays (n=11-16 mice/group) to assess various cognitive domains, including Y-maze, Novel Object Recognition, Barnes maze, and Nest Building at 1-, 2-, and 3-months post Ang II-infusion. We found that exposure of Ang II leads to deficits in spatial, recognition, and long-term memory evidenced by a reduction in spontaneous alternations in the Y-maze (52.44 ± 3.09 vs 63.00 ± 2.53%; p=0.0086), reduction in the discrimination index between the novel and familiar objects (0.1248 ± 0.046 vs 0.3478 ± 0.074; p=0.0354), and less time spent in the target quadrant where the escape hole used to be in the Barnes maze probe trial (60.57 ± 4.76 vs 78.98 ± 3.79 %; p=0.0060). We assessed if arterial stiffening impaired resting (CBF), measured by arterial spin labeling (ASL)-MRI, two months after Ang II infusion. We observed a drastic reduction in CBF in the hippocampus, an area important for learning and memory. Lastly, we were interested in whether arterial stiffening promoted neuroinflammation in the cortex and hippocampus. We performed immunohistochemistry for microglia (Iba1) and astrocytes (GFAP) to determine the presence of gliosis. Here, we found increased microglia-vascular interactions in the cortex of mice after 3 months of Ang II infusion compared to the saline. In conclusion, our study finds that arterial stiffening induced by a brief episode of hypertension causes cognitive impairment associated with a reduction in CBF and associated gliosis in the brain’s memory centers.