Low dose i.c.v. Ang II is associated with cognitive impairment and hyperphosphorylation of tau in male mice

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 3b (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. Blood pressure was recorded before minipump implantation and twice per week throughout the remainder of the experiment by tail-cuff plethysmography; however, blood pressure did not change across sexes and treatment groups (Treatment: p=0.51, Sex: p=0.07, Interaction: p=0.29; Three-Way Mixed ANOVA). To test for cognitive impairment, male and female 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). Yet, both male and female mice receiving low dose Ang II i.c.v. showed impaired nest building ability. 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 (sham: 262 ± 20.91 vs Ang II: 347.4 ± 30.41, n=6, p=0.04) in the cortex. Ongoing experiments seek to determine the extent of tau hyperphosphorylation and neuroinflammation in female mice treated with low dose Ang II in the absence of significant cognitive impairment. Future experiments will test whether tau-deficient mice treated with low dose Ang II are protected against the detrimental effects of i.c.v. infusion of low dose Ang II. In conclusion, our study suggests that brain Ang II contributes to the hyperphosphorylation of tau and cognitive impairment independently of an elevation in blood pressure. AHA 23SCEFIA1155595 AHA24DIVSUP1273494 T32HL144446 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.