Project Grant R21AG085331

REPROGRAMMING ENDOTHELIAL CELLS TO PREVENT AND TREAT ALZHEIMER DISEASE (AD) AND HYPERTENSION - PROJECT SUMMARY WENCESLAU, CAMILLA F. GROWING EVIDENCE SUPPORTS A ROBUST AND LIKELY CAUSAL ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE (CVD), AND ITS RISK FACTORS, WITH ALZHEIMER'S DISEASE (AD). HOWEVER, STANDARD PARADIGMS SUCH AS "HEAD TO HEART CONNECTION", WHERE HEART FAILURE LEADS TO CEREBRAL HYPOPERFUSION, NEURONAL DAMAGE AND, SUBSEQUENTLY AD ARE QUESTIONABLE, AND THEY SHOULD BE REVIEWED WITH A CRITICAL APPROACH. HERE, WE CLAIM THAT VASCULAR ENDOTHELIAL CELLS HAVE A CENTRAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF AD AND HYPERTENSION. OVER TIME, AS THE BODY AGES, THE VASCULATURE BECOMES LESS SUSCEPTIBLE TO REPAIR. ONE OF THE REASONS IS AN EXACERBATED ENDOTHELIAL-TO-MESENCHYMAL TRANSITION (ENDMT). ENDMT IS A CELLULAR TRANSDIFFERENTIATION PROGRAM IN WHICH ENDOTHELIAL CELLS PARTIALLY LOSE THEIR IDENTITY AND ACQUIRE MESENCHYMAL CELL- LIKE FEATURES AND THIS REDUCES BLOOD FLOW AND ORGAN PERFUSION. ONE OF THE TRIGGERS OF ENDMT IS ENDOPLASMIC RETICULUM (ER) STRESS, WHICH ALSO RELEASES MISFOLDED PROTEINS, INCLUDING AMYLOID-B PROTEIN OLIGOMERS (ABO), THE MOST POTENT NEUROTOXIN IN AD. HERE, WE OBSERVED THAT 1. DYSFUNCTIONAL VASCULAR TISSUE FROM HUMANS AND RODENTS RELEASES AND SENSES ABO. 2. VASCULAR DYSFUNCTION IS PROMINENT PRIOR TO THE ONSET OF AD. 3. INCREASED PLASMA LEVELS OF ABO ARE PRESENT IN HYPERTENSIVE MICE. 4. ABO INDUCED ER STRESS IN ENDOTHELIAL CELLS AND ER STRESS CAUSED THE FURTHER RELEASE OF ABO, SHOWING A POSITIVE FEEDFORWARD MECHANISM. THESE UNCONVENTIONAL OBSERVATIONS CALL FOR FURTHER ANALYSIS OF THE CAUSATIVE CONNECTION BETWEEN ENDOTHELIAL DYSFUNCTION AND AD. THEREFORE, THE OVERALL GOAL OF THIS EXPLORATORY AND DEVELOPMENTAL GRANTS (R21) PROJECT IS TO REPROGRAM ENDOTHELIAL CELLS FOR THE TREATMENT OF AD AND HYPERTENSION. FOR THIS, WE WILL TEST THE HYPOTHESES THAT THE CAUSE OF AD AND HYPERTENSION IS THE EXACERBATED FORMATION OF ENDMT VIA ER STRESS WHICH INCREASES THE SECRETION OF ABO. BY OVEREXPRESSING YAMANAKA FACTORS (OSK) TO INDUCE PARTIAL CELLULAR REPROGRAMMING, WITHOUT PASSING THROUGH THE PLURIPOTENT STATE, WE WILL REDUCE ENDMT FORMATION TO PREVENT AND REVERSE AD. WE ALSO WANT TO DETERMINE WHETHER ARTERY DYSFUNCTION IN HYPERTENSIVE MICE PRESENT WITH SIMILAR PHENOTYPE SEEN IN AD MICE. THIS PLANNED RESEARCH IS UNIQUELY SUITED TO THE R21 PROGRAM, RATHER THAN TO A TRADITIONAL GRANT (E.G., R01), BECAUSE IT EXPLORES AND OPENS A NEW AREA OF RESEARCH IN MY LABORATORY, BY STUDYING ENDMT AND YAMANAKA FACTORS AS THE UNDERPINNING OF AD. IF OUR HYPOTHESIS IS CORRECT, THIS PROJECT WILL PRODUCE A MAJOR IMPACT ON AD AND CVD.