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

Abstract

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.

The Potential of LPS-Binding Protein to Reverse Amyloid Formation in Plasma Fibrin of Individuals With Alzheimer-Type Dementia

“…However, we note that a control protein, such as human IgG should, in future, be used to present the specific effect of LBP on amyloid formation, to further elucidate the physiological processes discussed in this paper. In future, our hypothesis could also be tested in a transgenic murine model of AD (TgAD) or the 5xFAD (amyloid over-producing) model or equivalent ( Vale et al, 2010 ; Jeong et al, 2018 ).…”

New Insights Into the Pathogenesis of Alzheimer's Disease

“…GHSR1α may be a target for AD treatment. GHSR1α agonists such as MK0677 and LY444711 showed protective effects in animal and cell models (102,103). However, clinical trials of MK0677 in AD patients failed to show clinical benefit.…”

Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease

“…Recent findings identify MK-0677, a synthetic GHS-R agonist that crosses the BBB, as a potential therapeutic cognitive enhancer as it promoted the accumulation of α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor on excitatory hippocampal synapses and improved long term potentiation (LTP) 59 . Moreover, Jeong et al 110 showed that MK-0677 ameliorated Aβ deposition, neuroinflammation, and neurodegeneration in the 5xFAD mouse model of AD. In the APPSwDI mouse model of AD the GHS-R agonist, LY444711, improved spatial memory performance 111 .…”