Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep News and reviews Apelin, a promising target for Alzheimer disease prevention and treatment Javad Masoumi a,b , Morteza Abbasloui c , Reza Parvan d , Daryoush Mohammadnejad e , Graciela Pavon-Djavid f , Abolfazl Barzegari g , Jalal Abdolalizadeh e,c, ⁎ a Rafsanjan University of Medical Sciences, Rafsanjan, Iran b Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran c Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran d Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran e Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran f Unirversite Paris 13, Villetaneuse, France g Research Centre for Pharmaceotical Nanotechnology, Tabriz University (Medical Sciences), Tabriz, Iran ARTICLE INFO Keywords: Alzheimer disease Apelin Amyloid beta Central nervous system Oxidative stress ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative disease with high outbreak rates. It is estimated that about 35 million individuals around the world suffered from dementia in 2010. AD is expected to increase twofold every 20 years and, by 2030, approximately 65 million people could suffer from this illness. AD is determined clinically by a cognitive impairment and pathologically by the production of amyloid beta (Aβ), neurofibrillary tangles, toxic free radicals and inflammatory mediators in the brain. There is still no treatment to cure or even alter the progressive course of this disease; however, many new therapies are being investigated and are at various stages of clinical trials. Neuropeptides are signaling molecules used by neurons to communicate with each other. One of the im- portant neuropeptides is apelin, which can be isolated from bovine stomach. Apelin and its receptor APJ have been shown to broadly disseminate in the neurons and oligodendrocytes of the central nervous system. Apelin-13 is known to be the predominant neuropeptide in neuroprotection. It is involved in the processes of memory and learning as well as the prevention of neuronal damage. Studies have shown that apelin can directly or indirectly prevent the production of Aβ and reduce its amounts by increasing its degradation. Phosphorylation and ac- cumulation of tau protein may also be inhibited by apelin. Apelin is considered as an anti-inflammatory agent by preventing the production of inflammatory mediators such as interleukin-1β and tumor necrosis factor alpha. It has been shown that in vivo and in vitro anti-apoptotic effects of apelin have prevented the death of neurons. In this review, we describe the various functions of apelin associated with AD and present an integrated overview of recent findings that, in general, recommend apelin as a promising therapeutic agent in the treatment of this ailment. 1. Introduction Alzheimer's disease (AD) is a progressive neurodegenerative dis- order, and it is considered the most prevalent form of dementia in the elderly. Pathologically, it is characterized by intracellular neurofi- brillary tangles (NFTs) and extracellular amyloid beta (Aβ) protein deposits that contribute to senile plaques (Selkoe, 1991). The mutation in the amyloid precursor protein (APP), presenilin (PS) 1 and 2 genes https://doi.org/10.1016/j.npep.2018.05.008 Received 7 March 2018; Received in revised form 19 May 2018; Accepted 20 May 2018 ⁎ Corresponding author at: Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail address: abdolalizadehj@tbzmed.ac.ir (J. Abdolalizadeh). Abbreviations: AAA, Abdominal aortic aneurysm; ABCA1, ATP-binding cassette transporter A1; ACE, Angiotensin converting enzyme; ACh, Acetylcholine; AChE, Acetyl choline esterase; AD, Alzheimer's disease; ApoE, Apo lipoprotein E; AMPK, AMP-activated protein kinase; APP, Amyloid precursor protein; AT1R, Angiotensin II type 1 receptors; AVP, arginine vaso- pressin; Aβ, Amyloid beta; BACE1, β-site APP-cleaving enzyme 1/β-secretase; BBB, blood-brain barrier; CAT, Catalase; cGMP, Guanosine monophosphate; CNS, Central nervous system; eNO, Endothelial nitric oxide; eNOS, Endothelial nitric oxide synthase; ERK, Extracellular signal-regulated kinase; FDA, Food and Drug Administration; GLP-1, Glucagon-like peptide-1; GSH-Px, Glutathione peroxidase; GSK, Glycogen synthase kinase; H 2 O 2 , Hydrogen peroxide; I/R, Ischemia/reperfusion; ICAM-I, Intercellular adhesion molecule I; IFN, Interferon; IL, Interleukin; ICV, intracerebroventricular; IP 3 , Inositol triphosphate; JNK, c-Jun N-terminal kinase; LRP-1, Low-density lipoprotein receptor related protein-1; MAPK, Mitogen-activated protein kinase; MEK, Mitogen activated protein kinase kinase; MCP-1, Monocyte chemoattractant protein-1; MIP-1α, Macrophage inflammatory protein-1α; MPO, Myeloperoxidase; NEP, Neprilysin; NFT, Neurofibrillary tangles; NMDAR, N-methyl D-aspartate receptor; OxS, Oxidative stress; PI3K, phosphatidylinositide 3-kinases; PKB/AKT, Protein kinase B; PKC, Protein kinase C; PLA2, Phospholipase A2; PS, Presenilin; PTZ, Pentylenetetrazole; QUIN, Quinolinic acid; RAGE, Receptor for advanced glycation end products; RNS, Reactive nitrogen species; ROS, Reactive oxygen species; SD, Serum deprivation; SOD, Superoxide dismutase; TGF, Transforming growth factor; TNF-α, Tumor necrosis factor alpha Neuropeptides 70 (2018) 76–86 Available online 23 May 2018 0143-4179/ © 2018 Elsevier Ltd. 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