Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease

Abstract

Acyl-ghrelin (AG): A Form of ghrelin that has been acylated by GOAT, which enables it to bind to GHS-R1a. Acyl-protein thioesterase 1 (APT1): An endogenous enzyme known to de-acylate acylghrelin Allosteric mechanism: Regulation of a protein or receptor independent of its active site. Brain derived neurotrophic factor (BDNF): A growth factor in the brain, involved in cell proliferation, survival, learning and memory. Bromodeoxyuridine (BrdU): A synthetic thymidine analogue, incorporated into DNA during replication. It can be used as a marker of proliferation during a specific timeframe. Butyrylcholinesterase: An enzyme that hydrolyses many different choline-based esters, but can also de-acylate acyl-ghrelin, (AG) to form unacylated ghrelin (UAG). Endogenous esterase enzyme present in the plasma known to de-acylate acyl-ghrelin. Caloric restriction (CR): A reduction of food intake (typically 30% less) in the absence of malnutrition. Calorie Restriction mimetics: endogenous or exogenous factors that mimic the effects of CR cAMP response element binding protein (CREB): A transcription factor regulating BDNF expression and important in neuronal plasticity and memory. Dentate gyrus (DG): A sub-region of the hippocampus where neurogenesis occurs. Ghrelin-O-Acyl transferase (GOAT): a member of the membrane bound O-Acyl transferase (MBOAT) family, the only enzyme known to acylate ghrelin. GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR) receptors: Glutamate receptor and ion channels responsible for fast excitatory synaptic transmission. Important for synaptic plasticity and long-term potentiation (LTP). Growth hormone secretagogue receptor (GHSR): A G-protein-coupled receptor (GPCR) also known as the ghrelin receptor. It is the only known receptor for acyl-ghrelin. GHSR-eGFP mice: genetically mutated mice that co-express green fluorescent protein (GFP) with the Growth Hormone Secretagogue Receptor (GHS-R) gene Heterodimers: A protein complex, consisting of two different proteins. Hormesis: A bi-phasic dose-response to a drug or intervention, in which a low dose produces a beneficial effect and a high dose produces a harmful effect. Long-term potentiation (LTP): An important process in memory formation, resulting in a long-term increase in the strength of electrical activity or transmission between two neurones. Neural stem progenitor cells (NSPCs): Multipotent stem cells that reside in the brain with the capacity to differentiate into any neural cell type. Novel object recognition (NOR): Behaviour test of cognitive function that requires recognising novel from familiar objects. This is a hippocampal-dependent task. Passive avoidance learning (PAL): Behaviour test that evaluate memory and learning in rodents with neurological disorders. The rodents learn to avoid an environment in which an aversive stimulus was previously delivered. Pattern separation: The ability to distinguish similar inputs into separate discrete outputs. SAMP8 mice: a naturally occurring mouse model of accelerated ageing wi...

Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans

“…49 We therefore propose that acyl-ghrelin promotes hippocampal neurogenesis in a non-cell-autonomous manner. 22,50 To validate this, we show that acyl-ghrelin treatment of hippocampal NSPCs in vitro had no effect on cell proliferation-a result that was consistent with the absence of detectable GHS-R expression in these cells (Figure S7). To determine whether acyl-ghrelin and UAG directly affect the hippocampus, we treated primary hippocampal cultures, which contain a mixed population of cells, including neurons and NSPCs (Figure S6).…”

“…21 These studies clearly identify acyl-ghrelin as an important pro-neurogenic circulating factor. 22 In order to generate acyl-ghrelin, ghrelin must undergo post-translational acylation by the enzyme ghrelin-O-acyl transferase (GOAT), 23,24 prior to binding and activating GHS-R signaling. 25 Unacylatedghrelin (UAG) represents $80%-90% of circulating ghrelin and is often considered an inactive precursor to acyl-ghrelin.…”

Ghrelin attenuates drowning injury via dual effects on damage protection and immune repression

“…High levels of ghrelin influence the hypothalamus, thereby enhancing individual appetite. At the same time, ghrelin can also regulate the endocrine function and prevent depression after acting on the central nervous system (48,49). Recent studies have shown that ghrelin can regulate glucose and lipid metabolism by inhibiting insulin level in vivo (50,51).…”

Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

“…Notably, it has been postulated that GHS-R1α is, in fact, not present on immature neuroblasts and that AG possibly drives neurogenesis by stimulating the release of neurogenic factors by GHS-R1α-expressing adult dentate granule cells (Buntwal et al, 2019). Additional studies are needed to confirm these propositions in the hippocampus of healthy rodents and in vivo models of AD, however.…”