Temporal and Region‐Specific Tau Protein Hyper‐Phosphorylation in the Brain Coincides with the Development of Impaired Baroreflex Control of Arterial Pressure and Spatial Learning in Male Obese Zucker Rats

Abstract

Obesity and other traits of metabolic syndrome (MetS) are recognized risk factors for the development of neurodegenerative diseases such as Alzheimer’s Disease (AD) and related dementias. Emerging evidence indicates pathophysiologies common to MetS and AD, such as obesity, hypertension, insulin resistance, and impaired glycemic control, occur with development of tauopathies and cognitive decline. Male obese Zucker rats (OZRs), a hyperphagic genetic model of MetS, develop these deleterious traits with predictable ages of onset and time courses. Juvenile OZRs display prominently elevated triglycerides and insulin compared to age‐matched lean Zucker rats (LZRs). By 12‐14 weeks of age although fasting glucose is still comparable in OZRs and LZRs, with access to food the OZRs exhibit chronic, marked hyperglycemia. At this age male OZRs also become hypertensive with impaired short‐term control of arterial pressure by baroreflexes, which are improved by treatments that normalize blood glucose. We hypothesized that young adult male OZRs would develop age‐dependent expression of markers of neurodegeneration in medulla and hippocampus coincident with deficits in functions related to these brain regions. Cohorts of age‐matched male OZRs and LZRs underwent cognitive testing using the Morris water maze (MWM). At 18‐19 weeks, the escape latencies and path lengths were comparable in male OZRs and LZRs (n=12/group). In contrast, at 28 weeks of age, OZRs (n=16) exhibited a greater than 2‐fold higher escape latency and significantly longer path lengths (p<0.05) in the acquisition and retention phases of the MWM compared to age‐matched LZRs (n=15), suggesting the emergence of impaired spatial learning ability in the OZRs. The 18‐19‐week‐old male OZRs exhibited tau hyper‐phosphorylation (S396 and S199,and S202) in the medulla, but the expressions of these markers in the hippocampus were comparable in OZRs and LZRs (n=6/group) at this age. In contrast, 27‐28‐week‐old OZRs (n=6) exhibited tau hyperphosphorylation at S396in hippocampus as well as medulla compared to LZRs (n=6). Our data suggest that changes in tau phosphorylation in male OZRs occur in a temporal and spatial manner coincident with changes in brain function in these regions. In male OZRs, earlier manifestation in the medulla occurred with impaired short‐term regulation of arterial pressure by the medulla. Later manifestation of tau hyperphosphorylation in hippocampus coincided with deficits in spatial learning. Understanding mechanisms by which these histological, physiological, and behavioral changes occur in male OZRs may provide important insights into connections between the development of MetS and AD‐related dementias in humans to yield improved early‐stage interventions.