Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid β (Aβ1‐40) administration in mice

Abstract

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1-40 (Aβ ) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y-maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium-binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ blocked long-term potentiation induced by high-frequency stimulation and this effect could be acutely blocked with co-administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.

Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease

“…More specifically, acylghrelin increased cAMP response element binding protein (CREB) expression and led to the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and the promotion of brain derived neurotrophic factor (BDNF) expression in the hippocampus. Moreover, acylghrelin treatment of intrahippocampal amyloid-β injected mice, that mimic aspects of AD, rescued memory deficits 63,64 , decreased neuroinflammation 64 and prevented the amyloid-β induced suppression of hippocampal LTP 64 . Similarly, in amyloid-β injected rats treated with acyl-ghrelin there was a reduction in amyloid-β plaque deposition and attenuation of memory impairments due to increased AMP-activated protein kinase (AMPK) and glycogen synthase kinase (GSK) phosphorylation, and decreased tau phosphorylation 65 .…”

Neuropeptides Exert Neuroprotective Effects in Alzheimer's Disease

“…Central application of acylated ghrelin prevents Aβ-induced impairments of memory and energy and glucose metabolisms, probably through increase of AMPK and GSK phosphorylation and decrease of tau phosphorylation (Kang et al, 2015). Further study revealed that acylated ghrelin also blunts Aβ-induced depression of long-term potentiation (LTP) in hippocampus and therefore prevents impairments of recognition and spatial orientation (Santos et al, 2017). Ghrelin ameliorates neurogenesis impairment in hippocampus and improves memory deficits by prevention of synaptic degeneration including cholinergic fiber loss (Moon et al, 2011, 2014).…”

MK0677, a Ghrelin Mimetic, Improves Neurogenesis but Fails to Prevent Hippocampal Lesions in a Mouse Model of Alzheimer’s Disease Pathology

“…In previous studies, different groups have validated the beneficial effects of GHSR1α ligands, including ghrelin and acyl ghrelin, as well as GHSR1α agonists, including MK0677 and LY444711, on hippocampal neurogenesis, long-term potentiation, and cognition against Aβ toxicity in rodent models [14,16,18,55]. Although we have observed impaired neurogenesis in the dentate gyrus in 5xFAD mice and the neurogenic effect of MK0677 treatment, which is in agreement with a previous study [14], our results do not support the protective effect of GHSR1α activation against the development of Aβ-induced synaptic deficits or cognitive impairment.…”

“…Such discrepancies between previous studies and ours may arise from the use of different types of experimental systems. Two of the aforementioned studies employed Aβ 40 -or Aβ 42 -injected mouse or rat models [18,55]. The acute Aβ toxicity model may not represent the complexity of neuronal changes in response to chronic Aβ production and accumulation.…”

“…A previous study reported promoting effects of GHSR1α activation by ghrelin on hippocampal neurogenesis in a mouse model of brain amyloidosis (5xFAD mice) [14]. Additionally, several studies have shown that GHSR1α's natural ligand or agonists protect against Aβ toxicity-induced synaptic pathology and cognitive impairment in multiple lines of animal models mimicking AD pathology [15][16][17][18]. Notably, in a previous large-scale clinical trial, MK0677, a potent ghrelin mimetic, was found to be ineffective in mitigating cognitive impairment in AD patients [19].…”