MK-0677, a Ghrelin Agonist, Alleviates Amyloid Beta-Related Pathology in 5XFAD Mice, an Animal Model of Alzheimer's Disease

• Published in: International journal of molecular sciences Vol. 19; no. 6; p. 1800
• Main Authors: Jeong, Yu-On, Shin, Soo Jung, Park, Jun Yong, Ku, Bo Kyeong, Song, Ji Soo, Kim, Jwa-Jin, Jeon, Seong Gak, Lee, Sang Min, Moon, Minho
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18-06-2018; MDPI
• Subjects: 5XFAD mice; Accumulation; Adenosine monophosphate; Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer's disease; amyloid beta; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animal cognition; Animals; Apoptosis; Calcium; Cell cycle; Cyclic AMP; Dentate gyrus; Gene expression; Ghrelin; Ghrelin - agonists; Ghrelin - metabolism; Glial fibrillary acidic protein; Gliosis; Growth hormones; Hippocampus; Ibutamoren; Indoles - pharmacology; Indoles - therapeutic use; Inflammation; Kinases; Laboratory animals; Male; Memory; Mice; Mice, Inbred C57BL; MK-0677; Neocortex; Neocortex - drug effects; Neocortex - metabolism; Neurodegeneration; Neurogenesis; Neurological diseases; Neuronal-glial interactions; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Pathogenesis; Pathology; Peptides; Phosphorylation; Proteins; Rodents; Spiro Compounds - pharmacology; Spiro Compounds - therapeutic use; Stem cells; Stomach; Studies; Synaptophysin; Transgenic mice; United States > US; 5XFAD mice; MK-0677; ghrelin; Ibutamoren; Alzheimer disease; amyloid beta
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19061800

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and neuronal death. The primary pathogenic cause is believed to be the accumulation of pathogenic amyloid beta (Aβ) assemblies in the brain. Ghrelin, which is a peptide hormone predominantly secreted from the stomach, is an endogenous ligand for the growth hormone secretagogue-receptor type 1a (GHS-R1a). MK-0677 is a ghrelin agonist that potently stimulates the GHS-R1a ghrelin receptor. Interestingly, previous studies have shown that ghrelin improves cognitive impairments and attenuates neuronal death and neuroinflammation in several neurological disorders. However, it is unknown whether MK-0677 can affect Aβ accumulation or Aβ-mediated pathology in the brains of patients with AD. Therefore, we examined the effects of MK-0677 administration on AD-related pathology in 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD. MK-0677 was intraperitoneally administered to three-month-old 5XFAD mice. To visualize Aβ accumulation, neuroinflammation, and neurodegeneration, thioflavin-S staining and immunostaining with antibodies against Aβ (4G8), ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), neuronal nuclear antigen (NeuN), and synaptophysin were conducted in the neocortex of 5XFAD and wild-type mice, and to evaluate changes of phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) levels, immunostaining with antibody against pCREB was performed in dentate gyrus of the hippocampus of 5XFAD and wild-type mice. The histological analyses indicated that MK-0677-treated 5XFAD mice showed reduced Aβ deposition, gliosis, and neuronal and synaptic loss in the deep cortical layers, and inhibited the decrement of pCREB levels in dentate gyrus of the hippocampus compared to vehicle-treated 5XFAD mice. Our results showed that activation of the ghrelin receptor with MK-0677 inhibited the Aβ burden, neuroinflammation, and neurodegeneration, which suggested that MK-0677 might have potential as a treatment of the early phase of AD.