Tau Hyperphosphorylation in Brain Microvasculature: Relevance to Vascular Cognitive Impairment & Dementia (VCID)
Authors: KARAKAYA Eda , BERBER Burak , Kurtz John , Edwards Jazlyn , Albayram Onder , Ergul Adviye 
Published: May 2023

Current evidence suggests that cerebrovascular dysfunction including compromised BBB integrity and decreased CBF are early findings before the development of neuronal pathologies and cognitive deficits in VCID. Hyperphosphorylated tau (p-tau) is historically associated with the neurofibrillary tangles in AD but not in VCID. Notably, our recent study demonstrated that accumulation of non-fibrillar hyperphosphorylated tau (p-tau) is detectable in the brain microvasculature of VCID patients and contributes to the pathogenesis of dementia. Indeed, recent findings support that tau, being a microtubule-binding protein, is highly expressed in microvascular endothelial cells and its hyperphosphorylation leads to microtubule breakdown and disruption of barrier function. There is growing awareness that increased consumption of a high-fat diet (HFD) is believed to increase the risk for the development and progression of VCID, but the underlying mechanisms of how HFD leads to cognitive impairment are unclear, partly due to the use of different HFD models in preclinical studies. Palmitic acid (PA), the most common form of saturated fatty acid, found in the human cerebrospinal fluid in obesity, promotes disruption of BBB integrity. We hypothesized that a PA-rich diet mediates early disruption of blood brain barrier (BBB) integrity in part by endothelial tau hyperphosphorylation which leads to progressive neurovascular pathologies and cognitive impairment in VCID. Methods: 12-weeks old C57BL6/J mice were fed with 30% Kcal/weight PA-rich diet or matched purified diet. Open field behavior test was done 8 weeks after the start of diet. p-tau (ser214, ser262, AT8 and AT100) levels were measured in brain capillaries and homogenates isolated from animals at 8 weeks. In vitro studies included assessment of endothelial integrity by trans-endothelial electrical resistance (TEER), FITC measurements, cell viability, and expression levels of p-tau in human male brain microvascular endothelial cells (BMVECs) cultured in normal and high PA conditions. Results: Animals that were on the PA-rich diet exhibited risk-taking behavior (time spent in the center; 47.95 ±9.48, ** p<0.001). p-Tau (ser262) levels were higher in brain capillaries with the PA rich diet without any significant changes in brain homogenates (8.44±2.96, *p<0.05). BMVECs showed significantly increased permeability of FITC-dextran (36.28±0.05) and decreased TEER measurements (2744.24 ±80.83, ***p< 0.0001). With the PA treatment, BMVECs didn’t show significant change in p-Tau levels. Conclusion: A special PA-rich diet mediates an anxiety-like behavior as early as 7 weeks without any metabolic effects. Assessments at 22 and 24-weeks will determine whether behavioral dysfunction worsens and progresses to cognitive deficits. While in vitroresults suggest that disruption of barrier function is not associated with p-Tau under high PA-conditions, grea RF1 NS083559; R01 NS104573; R01 DE030313; VA Merit BX000347 & Senior Research Career Scientist Award IK6 BX004471. 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.