PROJECT SUMMARY/ABSTRACTAlzheimers disease (AD) is a progressive multifactorial disease affecting more than 50 million people worldwideand is the most common dementia of late-life. To date no interventions have demonstrated substantialtherapeutic efficacy to prevent delay or treat AD. In recent years both cardiovascular disorders (CVD) andgenetic factors (ApoE4) have been attributed to an increased risk of developing AD. The pathological arm of theRenin Angiotensin System (RAS) has been implicated in both CVD and AD whereas the protective armincluding Angiotensin (1-7)[A(1-7)] Mas receptor and ACE2 are known to counter-regulate these effects. A(1-7) through the Mas receptor is known to reduce inflammation and oxidative (OS) in several disease states andit also has regenerative effects by upregulating endogenous stem cell populations. Data from clinical studieshave shown that both A(1-7) and ACE2 are reduced in AD patients and several in-vivo studies support theefficacy of A(1-7) in treating AD. While the effects of A(1-7) in AD models have been extremely promising itsshort half-life and lack of oral bioavailability make it challenging to develop as a therapeutic modality. In order toovercome this shortcoming our lab has developed an equipotent small molecule analogues of A(1-7)RASRx1902 and RASRx1911. RASRx1902 and RASRx1911 have been shown to reduce inflammation and OSin target organs as well as having a regenerative effect on damaged tissues. A recent study from our lab showedthat RASRx1902 and RASRx1911 were able to improve cognitive function as well as reduce OS in the brain ina mouse model of hypertension induced cognitive dysfunction (transverse aortic constriction [TAC]). Since Masagonism is known to have a beneficial effect in AD we hypothesize that these molecules can be developed asa potential new therapeutic for the treatment of AD and related dementias. The primary objective of this proposalare to advance development of one small molecule Mas agonist to submission of an Investigation New DrugApplication (IND) for the treatment of AD and related dementias through: 1. Evaluation of the oral efficacy ofRASRx1902 and RASRx1911 in TAC and AD mouse models (5xFAD & ApoE4); 2. Assessment of the efficacyof RASRx1902 in TAC-ApoE4 mice 3. Scale up of one Mas agonist manufactured under Good ManufacturingPractices (GMP); 4. Development of a formulation of one Mas agonist for Phase I clinical trial; 5. Completion ofADME (PK) and IND-enabling Toxicology studies; 6. Preparation Pre IND and IND Documentation; 7. Conductof a Pre IND meeting; and 8. Filing of an IND. Research proposed herein is responsive to PAS 18-820 to developand evaluate therapies that prevent Alzheimer's disease (AD) slow its progression or treat its cognitive andbehavioral symptoms.