Abstract 068: Ang II i.c.v. is Associated with Cognitive Impairment and Tau Phosphorylation in Male Mice in the Absence of Hypertension

Hypertension is a known risk factor for cognitive impairment and dementia; however, there are significant gaps in knowledge regarding the brain-specific mechanisms by which hypertension contributes to dementia. Alzheimer’s disease (AD), the most common form of dementia in men and women, is characterized by aggregation of amyloid-beta plaques and hyperphosphorylation of the microtubule associated protein tau. Interestingly, the blood pressure regulating hormone angiotensin II (Ang II) can activate neuronal glycogen synthase kinase 3-beta (GSK-3b), a kinase known to be involved in the hyperphosphorylation of tau. Here we tested the hypothesis that brain Ang II can cause cognitive impairment by promoting tau hyperphosphorylation. 3-month-old male and female mice were treated with low dose Ang II (6 ng/h) or saline for 4 weeks via s.c. osmotic minipump connected to an i.c.v. cannula. Neither male nor female mice treated with low dose Ang II demonstrated an increase in systolic blood pressure (Treatment: p=0.51, Sex: p=0.07, Interaction: p=0.29, Three-Way Mixed ANOVA). To test for cognitive impairment, mice were subjected to a battery of behavior tests chosen to assay spatial working memory (Y-Maze), recognition memory (Novel Object Recognition), spatial learning and memory (Barnes Maze), and executive function (Nest Building). Male mice treated with low dose Ang II i.c.v. but not female mice demonstrated cognitive impairment with regards to recognition memory (NOR, sham: 0.37 ± 0.04 vs Ang II: 0.23 ± 0.06, n=20, p=0.0582) and spatial learning (Barnes Maze Learning Trials, Day 1: p=0.004 and Day 3: p=0.05). In male mice, cognitive impairment was associated with site specific tau phosphorylation (S404: p=0.03, T231: p=0.01, and T205: p=0.01) and increased microglial density in the cortex. (sham: 262 ± 20.91 vs Ang II: 347.4 ± 30.41, n=6, p=0.04) In a parallel experiment, male TauKO mice were also treated with low dose Ang II i.c.v. and were protected against cognitive impairment. In conclusion, our study suggests that brain Ang II, independent of the effects of hypertension, contributes to the hyperphosphorylation of tau and cognitive impairment in male mice.