Sex Differences in the Development of Impaired Spatial Learning and Tau Protein Hyper-Phosphorylation in Obese Zucker Rats

Metabolic syndrome is a cluster of co-occurring traits that elevate risk for development of neurodegenerative diseases such as Alzheimer’s Disease and related dementias. As seen in obese humans, young adult male obese Zucker rats (M-OZRs) develop dyslipidemia, insulin resistance, hyperglycemia, and hypertension with predictable onsets and time courses. By 12-16 weeks of age, M-OZRs also develop diminished baroreflex-mediated activation of the nucleus tractus solitarius (NTS) and short-term control of arterial pressure by baroreflexes compared to male lean OZRs (M-LZRs). At this age, hypertensive M-OZRs have normal fasting blood glucose that is chronically and substantially elevated with access to food compared to male lean Zucker rats (M-LZRs). We have shown that selective correction of this hyperglycemia with antidiabetic agents restores baroreflex-mediated activation of the NTS and baroreflexes in these hypertensive M-OZRs. In contrast, 16-week-old hypertensive female obese Zucker rats (F-OZRs) maintain normal fed glucose, baroreflex-mediated activation of the NTS, and baroreflexes compared to female lean Zucker rats (F-LZRs). However, by 27 weeks of age, F-OZRs develop impaired baroreflex bradycardia in the absence of fed hyperglycemia or diminished baroreflex-mediated activation of the NTS. We recently showed that young adult M-OZRs (17-19 weeks) have tau hyper-phosphorylation (S396 and S199, and S202) isolated to the NTS within the medulla coinciding with hypertension, diminished activation of the NTS and impaired baroreflexes. By 27-30 weeks of age, tau hyper-phosphorylation at S396 also emerges in the hippocampus of M-OZRs, coinciding with development of significantly impaired spatial learning abilities in the Morris water maze (MWM). Based on these findings, we hypothesized that tau hyper-phosphorylation at S396 would be absent in the medulla of 16-week-old F-OZRs with later development in the forebrain. Contrary to our hypothesis, 16-week-old F-OZRs had elevated tau protein expression (S396) in the medulla (p=0.025, n=7) and hippocampus (p=0.009, n=7) compared to F-LZRs. At this early age, F-OZRs also showed significantly increased escape latency and path length in the acquisition phase of MWM compared to F-LZRs (n=12/group, P<0.05). The presence of impaired spatial learning and elevated phosphorylated tau in medulla and hippocampus of 16-week-old F-OZRs in the absence of diminished baroreflexes or marked hyperglycemia suggests glucose and elevated arterial pressure variability are not essential driving factors for the development of these particular neurodegenerative markers or spatial learning deficits. Understanding mechanisms that underlie sex differences in the onset of neurodegenerative markers and impaired spatial learning in OZRs may aid in developing sex-specific therapeutic strategies for deficits with metabolic syndrome. Support: NIH R01HL132568-S1 to Dr. Ann Schreihofer. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.