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.
Highlights
Alzheimer’s disease (AD) is the most preeminent type of dementia
We examined the effects of MK-0677 on AD pathogenesis in 5XFAD mice
The thioflavin-S staining and immunohistochemical results revealed that MK-0677 reduced Aβ accumulation, neurodegeneration, and neuroinflammation in the 5XFAD mice, which suggested that MK-0677 ameliorated Aβ accumulation, as well as Aβ-induced pathogenesis
Summary
The number of Americans affected by AD is increasing exponentially and is expected to reach 13.8 million by 2050 from 5.4 million in 2016 [1,2]. AD results in various symptoms, such as memory impairments, language disturbances, and psychiatric problems [3]. The more AD progresses, the more daily functioning decreases and neuropsychiatric symptoms increase. According to the amyloid hypothesis, which is the most well-developed of the hypotheses of AD pathogenesis, deposits of the amyloid beta (Aβ) peptide are considered the major cause of the development of AD [4]. Aβ directly causes neurodegeneration, microgliosis, astrocytosis, neurofibrillary tangle deposition, and memory loss [4]. Targeting Aβ aggregation and Aβ-related pathologic changes has been suggested as a potential strategy for preventing AD pathogenesis
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