Angiotensin IV (AT4) is a hexapeptide (Val-Tyr-Ile-His-Pro-Phe) that has a wide range of activities in the central nervous system. There is evidence that the AT4 receptor (AT4R)is insulin-regulated aminopeptidase (IRAP).There is also evidence that AT4 interacts with the HGF system through the c-Met receptor. Synthetic small molecule analogues of AT4 with the ability to penetrate through blood brain barrier have been developed.

Alzheimer's (AD) and Parkinson's (PD) diseases are neurodegenerative diseases presently without effective drug treatments. AD is characterized by general cognitive impairment, difficulties with memory consolidation and retrieval, and with advanced stages episodes of agitation and anger. AD is increasing in frequency as life expectancy increases. Regarding the role of the brain renin–angiotensin system (RAS) in learning and memory and motor functions, with particular emphasis on research results suggesting a link between angiotensin IV interacting with the AT4 receptor subtype. Currently there is controversy over the identity of this AT4R protein. Convincing evidence has shown that it is the insulin-regulated aminopeptidase (IRAP). Recently members of our laboratory have presented evidence that the brain AT4/AT4R system coincides with the brain hepatocyte growth factor/c-Met receptor system. Synthesized small molecules of AT4-based peptides that are metabolically stable, penetrate the blood–brain barrier, and facilitate compromised memory and motor systems. Research efforts are described along with details concerning a synthesized molecule (tripeptide), Dihexa that shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses.

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Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. Ho JK, Nation DA. Neurosci Biobehav Rev. 2018 Sep;92:209-225. doi: 10.1016/j.neubiorev.2018.05.005. Epub 2018 May 4. Review. PMID: 29733881

Sex Difference of Angiotensin IV-, LVV-Hemorphin 7-, and Oxytocin-Induced Antiallodynia at the Spinal Level in Mice With Neuropathic Pain. Chow LH, Chen YH, Lai CF, Lin TY, Chen YJ, Kao JH, Huang EY. Anesth Analg. 2018 Jun;126(6):2093-2101. doi: 10.1213/ANE.0000000000002795. PMID: 29381512

Roles and functions of Atp6ap2 in the brain. Bracke A, von Bohlen Und Halbach O. Neural Regen Res. 2018 Dec;13(12):2038-2043. doi: 10.4103/1673-5374.241428. Review. PMID: 30323117 Free PMC Article

Within the Brain: The Renin Angiotensin System. Jackson L, Eldahshan W, Fagan SC, Ergul A. Int J Mol Sci. 2018 Mar 15;19(3). pii: E876. doi: 10.3390/ijms19030876. Review. PMID: 29543776 Free PMC Article

Sequences of Angiotensin Peptides

Angiotensin I: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

Angiotensin II: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin III: Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin IV: Val-Tyr-Ile-His-Pro-Phe