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

Abstract

Much thought has been given to the impact of Amyloid Beta, Tau and Alpha-Synuclein in the development of Alzheimer's disease (AD) and Parkinson's disease (PD), yet the clinical failures of the recent decades indicate that there are further pathological mechanisms at work. Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impaired neurogenesis and, of course, widespread axonal, synaptic and neuronal degeneration that leads to cognitive and motor impediments. Interestingly, the acylated form of the hormone ghrelin has shown the potential to ameliorate the latter pathologic changes, although some studies indicate a few complications that need to be considered in the long-term administration of the hormone. As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone's therapeutic benefits for the treatment of AD and PD.

Keywords: autophagy; dopamine; ghrelin; growth hormone secretagogue receptor 1 alpha; inflammation; insulin resistance; mitochondrial dysfunction; neurodegeneration.

Figure 1

Illustration of the neuroprotective pathways following GHS-R1α activation by AG or ghrelin agonists in neurons and astrocytes. [1] Mitochondrial function: By activating the key mediator AMPK, AG induces the transcriptional co-activator PGC1α. The latter, in concert with NRF1/2, enhances mitochondrial biogenesis, the synthesis of TFAM and TFAM-mediated mtDNA replication/transcription. By increasing the transcription of Mfn2, PGC1α protects from MPTP/rotenone-driven mitochondrial fragmentation. In addition, AMPK/GAPDH-mediated phosphorylation of nuclear SIRT1 frees the latter deacetylase and leads to the inactivation of pro-inflammatory NF-κB, the activation of the Bax-sequestrating Ku70 and the stimulation of FoxO1-regulated anti-oxidant and autophagy genes. Lastly, the induction of the AMPK/CPT1a/UCP2 pathway prevents pathological mitochondrial depolarization (such as by Aβ). Furthermore, UCP2-driven mitochondrial uncoupling increases the mitochondrial respiration, bioenergetic efficiency and mitigates the co-generation of ROS by the ETC, which may protect from the stress-induced hyperproduction of ATP and ROS during early stages of AD. Given that more advanced stages of AD are characterized by neuronal glucose hypometabolism and a chronic shift toward other bioenergetic processes, in particular the β-oxidation of lipids, AG may support the compensatory execution of β-oxidation to generate ATP. Notably, AMPK inhibits ACC, thus depleting the intracellular malonyl-CoA pools and, in turn, elevating the activity levels of the malonyl-CoA-regulated CPT1a (not shown). [2] Autophagy: (Macro)autophagy is primarily driven by the GHS-R1α/AMPK/TSC_1/2-mediated inactivation of mTOR/mTORC1 and the direct phosphorylation of ULK1 via AMPK, resulting in the degradation of cellular waste, amyloids (Aβ/Tau/α-synuclein) and defective mitochondria. Moreover, by raising the intracellular NAD⁺ levels, AMPK reinforces its activity through the activation of the cytoplasmic, NAD⁺-dependent SIRT1 and the AMPK-kinase LKB1. SIRT1 is also involved in the deacetylation of Tau at Lys¹⁷⁴, which was reported to abrogate the pathological propagation of Tau throughout the brain. Besides triggering autophagy, AG upregulates various ATGs and Beclin-1, while promoting autophagosome maturation and the autophagic flux. [3] Astrocytes: The stimulation of GHS-R1α encourages the expression of the lactate-efflux transporter MCT4 by astrocytes, leading to the increased secretion of lactate, a potent energy source for neurons.

Figure 2

Overview of the anti-inflammatory capabilities of GHS-R1α receptor activation. AD and PD are characterized by chronic systemic inflammation, which includes micro-/astrogliosis and inflammasome activation following the accumulation of amyloids and DAMPs in the CNS, vagus nerve and intestinal (microbiome) inflammation in the periphery as well as pathologic CD4⁺ T-cell infiltration into the brain, which is exacerbated by the inflammation-driven injury of the BBB and vasculature. While AG has successfully prevented neuroinflammation in AD and PD models, the diagram further illustrates the beneficial effects of AG on inflammasome induction, peripheral inflammation and adaptive immunity in other inflammatory disease models, which culminate in vascular protection as well as enhanced blood flow, BBB stability, insulin sensitivity, oligodendrocyte survival and axonal myelination. Of note, GHS-R1α does not appear to be expressed by microglia, suggesting that the anti-inflammatory benefits of AG in the CNS are indirect. Ghrelin agonists offer the additional benefit of blocking microglial CD36, thus inhibiting Aβ-elicited inflammation.

Figure 3

Depiction of the physiological dopamine transmission by AG from the SN to the dorsal striatum (nigrostriatal route) and the VTA to the nucleus accumbens and hippocampus (mesolimbic route). Notably, in addition to the loss of SN dopaminergic neurons and dopamine depletion in the dorsal striatum, PD patients exhibit neuronal degeneration in the VTA at a later stage, leading to bradyphrenia and dyskinesia. The mesocortical route of the VTA is not shown.