Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain

Abstract

Apelin, a peptide initially isolated from bovine stomach extract, is an endogenous ligand for the Apelin Receptor (APLNR). Subsequently, a second peptide, ELABELA, that can bind to the receptor has been identified. The Apelin receptor and its endogenous ligands are widely distributed in mammalian organs. A growing body of evidence suggests that this system participates in various signaling cascades that can regulate cell proliferation, blood pressure, fluid homeostasis, feeding behavior, and pituitary hormone release. Additional research has been done to elucidate the system's potential role in neurogenesis, the pathophysiology of Glioblastoma multiforme, and the protective effects of apelin peptides on some neurological and psychiatric disorders-ischemic stroke, epilepsy, Parkinson's, and Alzheimer's disease. This review discusses the current knowledge on the apelinergic system's involvement in brain physiology in health and disease.

Keywords: APJ; APLNR; Apelin; CNS; CNS-associated diseases; ELABELA; gene expression; neurogenesis.

Figure 1

Enzymatic processing of Apelin/ELABELA. (A). The inactive pre-proapelin (77aa) is processed via endogenous endonucleases to Apelin-55, which can bind to APLNR. Apelin-55 can be additionally processed, generating four isoforms: Apelin-13, Apelin-17, Apelin-36, and [Pyr¹] apelin-13. The generation of Apelin-13 is achieved by PCSK3 (FURIN). All four isoforms are capable of binding to the APLNR. CD10 (Neprilysin) is capable of inactivating [Pyr¹] apelin-13, creating two inactive Apelin-13 isoforms (5–13aa and 6–13aa). On the other hand, Angiotensin-converting enzyme 2 (ACE2) converts Apelin-13 and Apelin-36 to active forms, Apelin-13_(1–12) and Apelin-32_(1–35). (B). ELABELA gene codes for a non-functional 54aa-long pro-protein, which generates an active 32aa-long protein upon processing. ELABELA-32 can generate three fragments, ELABELA-11, an inactive form, generated with the help of PCSK3, and two functional ones, ELABELA_(1–9) and _(11–32), with the activity of unknown proteases. Abbreviations: PCSK3, proprotein convertases subtilisin/kexin type; CD10, Neprilysin; ACE2, Angiotensin Converting enzyme-2; KLKB1, Kallikrein.

Figure 2

Signaling pathways associated with activation of APLNR.

Figure 3

Expression of APLNR and Apelin ligand in the normal human brain. Schematic representation depicting the adult human brain at different levels showing the structures in which APLNR and Apelin ligand are expressed.