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

“, 2019), oxidative stress (Cenini et al., 2019), chronic systemic inflammation, pathological immune cell infiltration into the brain (Amor and Woodroofe, 2014; Anderson et al.”

“Thus, obesity and T2DMassociated hyperleptinemia (Maffei et al., 1995; Considine et al., 1996; Okumura et al., 2003; Pandey et al., 2015) may contribute to the desensitization of AG in the hypothalamus.”

“Furthermore, in IGF1-positive brain areas, the increased phosphorylation of Akt, enhanced levels of the apoptosis-suppressing protein Bcl-2 as well as the inactivation of the apoptosis-mediator Bad were detected (Datta et al., 1997).”

“Given the pivotal role of mitochondrial dysfunction in PD, toxins that are selectively taken up by dopaminergic neurons and impair mitochondrial complex 1, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), kill SN-located, dopaminergic neurons and induce Parkinsonism in humans and rodents (see Figure 2) (La…”

“, 2014), which is a master effector that upregulates ATP synthesis, curbs ATP utility, maintains the mitochondrial homeostasis and navigates mitophagy when the cellular energy stores are depleted (Herzig and Shaw, 2018).”

“, 2007) and deacetylates nuclear PGC1α to initiate mitochondrial biogenesis (Lagouge et al., 2006) as well as the transcription factor forkhead box protein O1 (FoxO1) to amplify the expression of PGC1α (Daitoku et al.”

“autophagy and, typically in response to stressful cellular conditions and starvation, the activating phosphorylation of the cytoplasmic energy-sensor AMPK results in the AMPK-mediated phosphorylation of TSC1/2 and the inhibition of mTORC1 (Inoki et al., 2003;Manning andCantley, 2003; Demetriades et al., 2016).”

“Thus, impairments in autophagy induce neurodegeneration independent of amyloid accumulation in affected brain areas (Hara et al., 2006; Komatsu et al., 2006).”

“Thus, obesity and T2DMassociated hyperleptinemia (Maffei et al., 1995; Considine et al., 1996; Okumura et al., 2003; Pandey et al., 2015) may contribute to the desensitization of AG in the hypothalamus.”

“, 2016), vascular abnormalities, reduced blood flow, blood brain barrier (BBB) damage (Kisler et al., 2017; Sweeney et al., 2018), dysfunctional autophagy and mitophagy (Kerr et al.”

“Mature ghrelin is stored within secretory granules of X/A-like cells and released into the bloodstream upon fasting to stimulate appetite (Cummings et al., 2001; Yanagi et al., 2018).”

“To recharge NAD and FAD and to resume ATP generation, the brain relies on glucose as major energy substrate as well as its metabolization in the tricarboxylic acid cycle (TCA) as main bioenergetic pathway (Penicaud et al., 2002; Arun et al., 2016; Martinez-Reyes and Chandel, 2020).”

“AG-driven autophagy is dependent on the stimulation of AMPK, leading to increased levels of ATG5, ATG7, ATG12, and Beclin-1, lessened p62 levels (an autophagy marker that is adversely correlated with autophagy), an elevated microtubule-associated protein light chain 3 (LC3)-II/LC3-I ratio, which serves as a marker to…”

“Furthermore, the reduced expression of GHS-R1α was verified in induced pluripotent stem cells with a mutated or disrupted PARK2 gene, which is a mitochondrial gene implicated in mitochondrial quality control, mitophagy, and the development of early-onset PD (Pickrell and Youle, 2015), and in the SNpc of an in vivo mod…”

“Importantly, DAG is incapable of interacting with GHSR1α, yet the existence of distinct DAG-binding receptors has been postulated (Howard et al., 1996; Yanagi et al., 2018).”

“Similarly, obese individuals and patients with metabolic syndrome displayed reduced plasma ghrelin pools (Tschop et al., 2001; Rigamonti et al., 2002; Shiiya et al., 2002; Tesauro et al., 2005).”

“Ghrelin is predominantly produced by gastric X/A-like cells that are located in the oxyntic gland of the stomach (Date et al., 2000), although a lower degree of the hormone is also expressed in various peripheral tissues, in lymphocytes and in the CNS (Ferrini et al.”

“, 2004) or DNA repair factor Ku70, which was shown to scavenge proapoptotic Bax from mitochondria to support cellular survival (Cohen et al., 2004).”

“Moreover, the rate of inhibitory serine phosphorylation of IRS1 (as a marker of insulin resistance), independent of even T2DM or the APOEε4 allele, rose gradually from previously healthy suspects to mild cognitive impairment (MCI) to AD patients, correlated with the quantity of Aß deposits and was inversely associated…”

“As expected, mitophagy is widely impaired in respective models as well as in the brains of AD and PD patients, while the selective pharmacological enhancement of mitophagy can reverse several other pathological aspects, such as the generation of insoluble Aβ, Tau hyperphosphorylation, neuroinflammation, neuronal atrop…”

“Such and related investigations led to the designation of AD as “type 3 diabetes” (Steen et al., 2005; Moloney et al., 2010).”

“Therefore, in general, AG induces intraneuronal Ca2+ accumulation in an IP3-mediated manner, leading to the activation of the AMPKphosphorylating calmodulin-dependent protein kinase kinase-β (CaMKKß) (Hawley et al., 2005; Anderson et al., 2008).”

“This results in the intraneuronal accumulation of non-degraded and amyloid-containing autophagosomes, co-localizing strongly with neurons that display intracellular Tau pathology and the relative loss of mitochondria and other organelles (Cataldo et al., 1994; Nixon et al., 2005).”

“GHS-R1α is widely transcribed in multiple key areas of the brain, such as the hippocampus, hypothalamus, cortex, ventral tegmental area (VTA), SN, spinal cord, dorsal and median raphe nuclei, sympathetic preganglionic nerves and endothelial cells of the cerebral vasculature, yet it is also expressed by various immune…”

“Over time, prolonged neuroinflammation encourages various other secondary complications, such as impairments in protein degradation, amyloid misfolding, Tau hyperphosphorylation (in conjunction with the inflammationperpetuating activation of the inflammasome), permeabilization of the BBB, peripheral immune cell infilt…”

“Shut-down of the growthfacilitating mTORC1 pathway, however, promotes the activity of the unc-51 like autophagy activating kinase (ULK1/2) initiation complex, which launches autophagosome maturation and the cellular purging of waste products, such as Aß, Tau or αsynuclein (Huang and Manning, 2008; Ma and Blenis, 2009;…”

“Nonetheless, AD patients showed a massive decline in the transcriptional levels of the autophagy initiator Beclin1 during early stages of AD and strategies that have aimed to enhance the degree of autophagy, such as the lentivirusmediated expression of Beclin 1 or the autophagy-inducing blockage of mTor by rapamycin,…”

“GHS-R1α is widely transcribed in multiple key areas of the brain, such as the hippocampus, hypothalamus, cortex, ventral tegmental area (VTA), SN, spinal cord, dorsal and median raphe nuclei, sympathetic preganglionic nerves and endothelial cells of the cerebral vasculature, yet it is also expressed by various immune…”

“Regarding immune infiltration, CD4+ T-cell-deleted mice were shown to be protected from MPTP-triggered neurodegeneration, proposing that the adaptive immune system is heavily involved in PD pathology (Brochard et al., 2009).”

“In contrast, the inhibition of lysosome-associated proteolytic enzymes was capable of producing an AD-like phenotype (Boland et al., 2008).”

“This is in line with the Mfn2-upregulating and Drp1-impeding function of PGC-1α (Peng et al., 2017), suggesting that AG stimulates the AMPK/PGC-1α axis to ameliorate mitochondrial fragmentation in response to cellular stress (Sirago et al., 2017).”

“Moreover, AG downregulated the transcription of IL-1 and/or the inflammasome-activating cytokine TNF-α in face of MPTPinjury (PD), threohydroxyaspartate (THA)/kainic acid-assault (excitotoxicity), subarachnoid hemorrhage and SCI (Moon et al., 2009a; Ersahin et al., 2010; Lee J. et al., 2010; Lee et al., 2012, 2014b; A…”

“Acylated Ghrelin Induces Dopamine Transmission in the Ventral Tegmental Area and Stimulates Locomotor Activity and Memory Noteworthy, GHS-R1α was found to be expressed by ∼60% of dopaminergic neurons in the VTA of rats (Abizaid et al., 2006).”

“, 2019), chronic systemic inflammation, pathological immune cell infiltration into the brain (Amor and Woodroofe, 2014; Anderson et al., 2014; Stephenson et al., 2018), inflammasome activation (Ising et al.”

“Depending on the presence or absence of the acyl group at Ser3, mature ghrelin can be further distinguished into its active form, acylated ghrelin (AG), and desacylated ghrelin (DAG) (Hosoda et al., 2000; Yanagi et al., 2018).”

“Moreover, the administration of LPS into older animals, which display lessened expression of GHS-R1α in the DVC, evoked the excessive release of TNF-α and IL-6, far greater than in younger littermates (Wu et al., 2009b).”

“Furthermore, in vitro studies have shown that the administration of AG downregulated the synthesis of IL-1β, IL-6, and TNFα in human peripheral blood mononuclear cells following irritation with the mitogen phytohemagglutinin (Dixit et al., 2004).”

“Additionally, a high-fat diet, in an inflammation-mediated manner, promotes hypothalamic leptin resistance as well (El-Haschimi et al., 2000; Zhang et al., 2008).”

“In addition, heightened numbers of partially α-synuclein-reactive Th17 cells were discovered in the blood of PD patients (Sulzer et al., 2017); to the degree that PD has been postulated as an α-synuclein-reactive autoimmune disease (Benner et al., 2008; Hu, 2011).”

“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, impai…”

“Furthermore, AMPK phosphorylates glyceraldehyde 3- phosphate dehydrogenase (GAPDH) at Ser122 during starvation to encourage the nuclear trafficking of GAPDH and the displacement of SIRT1 from its repressor Deleted in Breast Cancer 1 (DBC1) (Chang et al., 2015).”

“This indicates that, similar to AD, autophagosomal efficiency is lost during PD, leading to the amassment of defective, waste-cluttered lysosomes and the failure of amyloid clearance (Chu et al., 2009; Alvarez-Erviti et al., 2010; Dehay et al., 2010).”

“Moreover, SIRT1 is capable of shuttling between the cytoplasm and nucleus (Tanno et al., 2007) and deacetylates nuclear PGC1α to initiate mitochondrial biogenesis (Lagouge et al.”

“, 2019), with NF-κB driving the synthesis of the inflammasome sensor NLRP3 as well as the pro-inflammatory cytokines pro-IL1/IL-1, pro-IL-18, TNF-α and many more (Afonina et al., 2017).”

“Such and related investigations led to the designation of AD as “type 3 diabetes” (Steen et al., 2005; Moloney et al., 2010).”

“For instance, a highfat diet, which induces systemic insulin resistance, was shown to attenuate neuroprotective brain-derived neurotrophic factor levels, long-term potentiation (LTP) and dendritic spine density in the hippocampus of previously healthy mice, while accelerating Aβ plaque formation and memory loss in Aβt…”

“Therefore, monotherapies are presumably an ineffective way of approaching AD and PD and are more likely to fail, supporting the concept that multi-targeted therapies are more profitable (Iqbal and Grundke-Iqbal, 2010; Adams, 2020; Huang et al., 2020).”

“As such, the function of variousmitochondrial master modulators, including AMPK and PGC1α, is disturbed in AD and PD.”

“Additionally, a high-fat diet, in an inflammation-mediated manner, promotes hypothalamic leptin resistance as well (El-Haschimi et al., 2000; Zhang et al., 2008).”

“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, impai…”

“For instance, a highfat diet, which induces systemic insulin resistance, was shown to attenuate neuroprotective brain-derived neurotrophic factor levels, long-term potentiation (LTP) and dendritic spine density in the hippocampus of previously healthy mice, while accelerating Aβ plaque formation and memory loss in Aβt…”

“For instance, the administration of AG succeeded in the animal model of colitis, showing downregulated local and systemic release of pro-inflammatory modulators, reduced inflammatory Th 1 activity, elevated action of immunosuppressive regulatory T-cells (Tregs), diminished oxidative stress, ameliorated intestinal tiss…”

“…(Muddapu et al., 2020), as evident in the brains of both AD (Lyingtunell et al., 1981; Hoyer et al., 1988; Ogawa et al., 1996; Drzezga et al., 2003; Mosconi et al., 2008) and PD patients (Huang et al., 2008; Hosokai et al., 2009; Liepelt et al., 2009; Borghammer et al., 2010; Berti et al., 2012).”

“The mitochondrial pathology in AD and PD is further exacerbated by impaired mitochondrial biogenesis, a mechanism that leads to the generation of additional mitochondria to meet greater energetic demands in cells, and mitophagy, which is a form of autophagy that mediates the degradation of malfunctional, ROS-overprodu…”

“While mutant α-synuclein enhances mitochondrial fragmentation, impairs the mitochondrial respiratory activity and induces neuronal death by inducing the displacement of wt α-synuclein from the inner-mitochondrial membrane (Kamp et al., 2010; Nakamura et al., 2011; Guardia-Laguarta et al., 2014), it must be noted that…”

“The NTS, on the other hand, further projects across the entirety of the CNS, ultimately leading to the intestinal return of immune-suppressing signals through the afferent ends of the vagal nerve.”

“In accord with insulin resistance, glucose hypometabolism in the CNS, for instance within the cortex, has been linked to the transition from MCI to AD and cognitive dysfunction (Lyingtunell et al., 1981; Hoyer et al., 1988; Ogawa et al., 1996; Drzezga et al., 2003; Mosconi et al., 2008).”

“As such, the function of variousmitochondrial master modulators, including AMPK and PGC1α, is disturbed in AD and PD.”

“The latter may be another consequence of insulin resistance, since insulin promotes the cerebral blood flow by enhancing NOdriven vasoconstriction and endothelin 1-mediated capillary recruitment (Craft, 2009).”

“, 2011), hence the loss of insulin signaling initiates Tau hyperphosphorylation and aggregation in AD (Hong and Lee, 1997; Schubert et al., 2003, 2004).”

“, 2010) and, under conditions of cellular stress, FoxO1 drives the transcription of various anti-oxidant enzymes, such as the PGC1α-co-activated, mitochondrialMnSOD (St.-Pierre et al., 2006; Hsu et al., 2010; Tong et al., 2012).”

“Since DAG failed to modify inflammatory reactions by HUVECs, it was implied that the described inflammation-dampening effects were reliant on GHS-R1α (Li et al., 2004).”

“This indicates that, similar to AD, autophagosomal efficiency is lost during PD, leading to the amassment of defective, waste-cluttered lysosomes and the failure of amyloid clearance (Chu et al., 2009; Alvarez-Erviti et al., 2010; Dehay et al., 2010).”

“Evidence that Acylated Ghrelin Opposes the Activation of the Inflammasome in the Brain The stimulation of the inflammasome and the associated pyroptosis, the “fiery death” of microglia, oligodendrocytes and other cells, a relatively recent upbringing, have been identified as major drivers of neuroinflammation, demyeli…”

“While mutant α-synuclein enhances mitochondrial fragmentation, impairs the mitochondrial respiratory activity and induces neuronal death by inducing the displacement of wt α-synuclein from the inner-mitochondrial membrane (Kamp et al., 2010; Nakamura et al., 2011; Guardia-Laguarta et al., 2014), it must be noted that…”

“Given the pivotal and neuroprotective role of insulin-signaling in the brain and that T2DM is one of the greatest known risk factors for AD and PD, it is no surprise that its early desensitization in the CNS, believed to predominantly occur in response to chronic inflammation, promotes the development of AD and PD (se…”

“This receptor has been reported to act as an inflammatory conductor for Aß, leading to the production of ROS and proinflammatory cytokines upon the interaction of fibrillar Aß with microglial or macrophage CD36 (Coraci et al., 2002; Bamberger et al., 2003; El Khoury et al., 2003; Demers et al., 2004).”

“In the other hand, AG does not modulate FAS in other brain areas, including the amygdala, striatum, hippocampus, several cortical regions and others (Lopez et al., 2008; Yanagi et al., 2018).”

“Furthermore, pathogen-associated molecular patterns (PAMPs) that originate from cerebral infections, such as LPS, or, in the case of AD, infections with members of the Herpesviridae family and Hepatitis C virus, may further potentiate neuroinflammation (Morales et al., 2014; Sochocka et al., 2017; Cortes et al., 2018;…”

“…in mitochondria-associated genes protect from MPTP oxidative assault in cell and animal models of PD, whereas the deletion of PGC1α exacerbates MPTP-induced injury and excitotoxicity (Scarpulla, 2002, 2006; Kang and Hamasaki, 2005; St.-Pierre et al., 2006; Mudo et al., 2012; Quan et al., 2020).”

“While mutant α-synuclein enhances mitochondrial fragmentation, impairs the mitochondrial respiratory activity and induces neuronal death by inducing the displacement of wt α-synuclein from the inner-mitochondrial membrane (Kamp et al., 2010; Nakamura et al., 2011; Guardia-Laguarta et al., 2014), it must be noted that…”

“In the periphery, for example, independent of the hormone’s orexigenic effects, AG stimulated the expression of lipogenic enzymes (fatty acid synthase (FAS), lipoprotein lipase and more) and lessened the transcription of carnitine palmitoyltransferase Ia (CPT1a), a ratelimiting effector necessary to induce fatty acid…”

“As a word of caution, while the β-oxidation of lipids has been proven in astrocytes, its utility by neurons is yet to be verified (Tracey et al., 2018).”

“and OPA1 ameliorated excessive mitochondrial fission and impaired ATP production in PINK1/Parkin-mutant cells (Lutz et al., 2009) and shielded against MPTP-driven mitochondrial fragmentation, the stimulation of the pro-apoptotic activity of p53, Bax and PUMA, dopaminergic neuron and nerve terminal loss as well as moto…”

“This receptor has been reported to act as an inflammatory conductor for Aß, leading to the production of ROS and proinflammatory cytokines upon the interaction of fibrillar Aß with microglial or macrophage CD36 (Coraci et al., 2002; Bamberger et al., 2003; El Khoury et al., 2003; Demers et al., 2004).”

“Moreover, it has been strongly implied that CD4 T helper (Th)1 and Th17 cells, for instance immunoreactive against α-synuclein, are the main lymphocyte populations that contribute to the death of dopaminergic neurons (Brochard et al., 2009; Reynolds et al., 2010).”

“, 2013) and the stimulation of AMPK was proven to trigger the AMPKconveyed activating phosphorylation of eNOS at Ser1177 in cultured human and rat endothelial cells, thus strengthening vasodilation in vivo (Morrow et al., 2003; Suzuki et al., 2008), it is highly likely that the AG-evoked liberation of NO is”

“, 2014a), the MMP family member that directly proteolyzes BBB components (Lakhan et al., 2013).”

“…in mitochondria-associated genes protect from MPTP oxidative assault in cell and animal models of PD, whereas the deletion of PGC1α exacerbates MPTP-induced injury and excitotoxicity (Scarpulla, 2002, 2006; Kang and Hamasaki, 2005; St.-Pierre et al., 2006; Mudo et al., 2012; Quan et al., 2020).”

“Furthermore, GHS-R1α antagonists, GOAT inhibitors and the genetic deletion of GHS-R1α enhanced the release of insulin, glucose tolerance, insulin sensitivity and weight loss in in vivo models of obesity (Sun et al., 2006; Esler et al., 2007; Longo et al., 2008; Barnett et al., 2010; Qi et al., 2011).”

“, 2017); to the degree that PD has been postulated as an α-synuclein-reactive autoimmune disease (Benner et al., 2008; Hu, 2011).”

“Such findings indicate that autophagy-enhancing approaches must ensue early, since the mere upregulation of autophagy is insufficient at an advanced stage of AD, when insoluble and proteolysis-resistant aggregates have already formed in the brain (Majumder et al., 2011).”

“Over time, prolonged neuroinflammation encourages various other secondary complications, such as impairments in protein degradation, amyloid misfolding, Tau hyperphosphorylation (in conjunction with the inflammationperpetuating activation of the inflammasome), permeabilization of the BBB, peripheral immune cell infilt…”

“A Possible Implication of Acylated Ghrelin in the Enhancement of Mitochondrial Fusion and Fission Unsurprisingly, in accordance with general mitochondrial dysfunction, the efficiency of mitochondrial fusion and fission gradually declines during the aging process and is disturbed in neurodegenerative diseases (Liu et a…”

“Additionally, the co-emergence of insulin resistance, leading to reductions in PI3K/Akt/mTORC1-driven protein translation in dopaminergic neurons (Athauda and Foltynie, 2016; Anandhan et al., 2017; Holscher, 2019), presumably aggravates dopaminergic dysfunction and neuronal insensitivity toward AG.”

“…deacetylation halflife times (t1/2) of 4 h or 6.4 h, respectively, have been reported for AG in human plasma and∼27min in rat serum, whereas the degradation t1/2 of total circulatory ghrelin has been estimated to be as short as ∼9-11min (De Vriese et al., 2004; Liu et al., 2008; Tong et al., 2013).”

“Jointly, the PGC1α-induced transcriptional changes in mitochondria-associated genes protect from MPTP oxidative assault in cell and animal models of PD, whereas the deletion of PGC1α exacerbates MPTP-induced injury and excitotoxicity (Scarpulla, 2002, 2006; Kang and Hamasaki, 2005; St.-Pierre et al., 2006; Mudo et al.…”

“Moreover, AG downregulated the transcription of IL-1 and/or the inflammasome-activating cytokine TNF-α in face of MPTPinjury (PD), threohydroxyaspartate (THA)/kainic acid-assault (excitotoxicity), subarachnoid hemorrhage and SCI (Moon et al., 2009a; Ersahin et al., 2010; Lee J. et al., 2010; Lee et al., 2012, 2014b; A…”

“GSK3β is a Tau-phosphorylating kinase whose activity is aberrantly enhanced in response to the desensitization of insulin and the associated loss of Akt-signaling during diabetes mellitus and AD (Jolivalt et al., 2008; Zhang et al., 2018).”

“GSK3β is a Tau-phosphorylating kinase whose activity is aberrantly enhanced in response to the desensitization of insulin and the associated loss of Akt-signaling during diabetes mellitus and AD (Jolivalt et al., 2008; Zhang et al., 2018).”

“GHS-R1α is widely transcribed in multiple key areas of the brain, such as the hippocampus, hypothalamus, cortex, ventral tegmental area (VTA), SN, spinal cord, dorsal and median raphe nuclei, sympathetic preganglionic nerves and endothelial cells of the cerebral vasculature, yet it is also expressed by various immune…”

“…insulin (Gault and Holscher, 2018; Holscher, 2019), as well as alterations of the dopaminergic system, including the extensive atrophy of substantia nigra pars compacta (SNpc)-located dopaminergic neurons and dopamine depletion in the striatum in PD (Martorana and Koch, 2014; Poewe et al., 2017).”

“, 2018), or DAG, to prevent AGencouraged glucose intolerance and hypoinsulinemia (Gauna et al., 2004; Kiewiet et al., 2009), may be profitable.”

“For instance, the administration of AG succeeded in the animal model of colitis, showing downregulated local and systemic release of pro-inflammatory modulators, reduced inflammatory Th 1 activity, elevated action of immunosuppressive regulatory T-cells (Tregs), diminished oxidative stress, ameliorated intestinal tiss…”

“…GHS-R1α antagonists, GOAT inhibitors and the genetic deletion of GHS-R1α enhanced the release of insulin, glucose tolerance, insulin sensitivity and weight loss in in vivo models of obesity (Sun et al., 2006; Esler et al., 2007; Longo et al., 2008; Barnett et al., 2010; Qi et al., 2011).”

“On the other hand, it must be noted that the prevalence of cerebral insulin resistance during AD leads to defects in the metabolism of glucose, which is believed to provoke the use of β-oxidation and lipids (ketones) as primary energy sources for neurons (Neth and Craft, 2017).”

“In such AD in vivo models, AG rescued from hippocampal atrophy, synaptic damage and the degeneration of cholinergic projections, heightened brain glycogen levels, diminished Aß aggregation and deposition, blocked Aβimparted deficits in LTPs, normalized plasticity-associated p-CREB levels, improved insulin sensitivity,…”

“As such, the function of variousmitochondrial master modulators, including AMPK and PGC1α, is disturbed in AD and PD.”

“As concluded elsewhere in the context of colitis, the inflammation-ameliorating mechanisms of AG include (i) the attenuation of systemic innate and adaptive immune responses, which is dependent on the direct suppression of leukocytes; (ii) the AG-stimulated liberation of tissue-strengthening GH and insulin-like growth…”

“The mitochondrial pathology in AD and PD is further exacerbated by impaired mitochondrial biogenesis, a mechanism that leads to the generation of additional mitochondria to meet greater energetic demands in cells, and mitophagy, which is a form of autophagy that mediates the degradation of malfunctional, ROS-overprodu…”

“In concert, the area postrema, the nucleus tractus solitarius and the dorsal motor nucleus of the vagus (DMV) form the dorsal vagal complex (DVC) that serves as a commanding platform for the autonomic nervous system, navigating gastrointestinal motility, secretory activity and pancreatic hormone release (Price et al.,…”

“A clinical trial, although slightly underpowered, has indicated that the injection of the ghrelin analog MK-677 proved to sustain IGF1 release in the long-term, which led to enhancements in the lean body mass of healthy, aged and non-obese subjects after a 1-year treatment period (Nass et al., 2008).”

“4 h, respectively, have been reported for AG in human plasma and∼27min in rat serum, whereas the degradation t1/2 of total circulatory ghrelin has been estimated to be as short as ∼9-11min (De Vriese et al., 2004; Liu et al., 2008; Tong et al., 2013).”

“Furthermore, the cerebral infusion of LPS, in a mostly MMP-3-conyeyed manner, injured the BBB through the upregulation of MMP-3, MMP9, and the MMPdriven degradation of various tight junction proteins in rodents (Gurney et al., 2006).”

“Moreover, AG downregulated the transcription of IL-1 and/or the inflammasome-activating cytokine TNF-α in face of MPTPinjury (PD), threohydroxyaspartate (THA)/kainic acid-assault (excitotoxicity), subarachnoid hemorrhage and SCI (Moon et al., 2009a; Ersahin et al., 2010; Lee J. et al., 2010; Lee et al., 2012, 2014b; A…”

“Furthermore, GHS-R1α antagonists, GOAT inhibitors and the genetic deletion of GHS-R1α enhanced the release of insulin, glucose tolerance, insulin sensitivity and weight loss in in vivo models of obesity (Sun et al., 2006; Esler et al., 2007; Longo et al., 2008; Barnett et al., 2010; Qi et al., 2011).”

“Therefore, monotherapies are presumably an ineffective way of approaching AD and PD and are more likely to fail, supporting the concept that multi-targeted therapies are more profitable (Iqbal and Grundke-Iqbal, 2010; Adams, 2020; Huang et al., 2020).”

“Interestingly, various studies have indicated that PD patients also exhibit cortical glucose hypometabolism and diminished blood flow in this area (Huang et al., 2008; Hosokai et al., 2009; Liepelt et al., 2009; Borghammer et al., 2010; Berti et al., 2012), a decreased rate of glucose consumption in the frontal lobe a…”

“Further in vivo studies in the MPTP model support the idea that, in conjunction with BBB injury and the loss of tight junction proteins in the nigrostriatal area, the pathological infiltration of lymphocytes and other immune cells as well as the T-cell-driven induction of microglia occur in the SN (Kurkowska-Jastrzebs…”

“, 2009), whereas the enhanced transcription of TLR2 and TLR4 have been detected in α-synuclein and MPTP mouse models of PD (Panaro et al., 2008; Letiembre et al., 2009), indicating that immune regulation is harmfully altered in AD and PD.”

“In accord with insulin resistance, glucose hypometabolism in the CNS, for instance within the cortex, has been linked to the transition from MCI to AD and cognitive dysfunction (Lyingtunell et al., 1981; Hoyer et al., 1988; Ogawa et al., 1996; Drzezga et al., 2003; Mosconi et al., 2008).”

“In any way, the desensitization of insulin in the CNS is linked to reduced cerebral glucose uptake, the diminished liberation of lactate, another pivotal energy source for neurons, by astrocytes and chronic glucose hypometabolism (Muddapu et al., 2020), as evident in the brains of both AD (Lyingtunell et al.”

“, 2015) as well as the reduced expression of glycolytic enzymes in the putamen and the cerebellum (Dunn et al., 2014).”

“, 2018) and primary hypothalamic neurons during oxygen and glucose withdrawal (Chung et al., 2007).”

“…overexpression of Beclin 1 or the utility of the autophagy-activator and mTor-inhibitor rapamycin rescued the apoptosis of dopaminergic neurons in response to the loss of proteasomal function or the accumulation of α-synuclein in cells and animals (Pan et al., 2008; Spencer et al., 2009).”

“Nonetheless, AD patients showed a massive decline in the transcriptional levels of the autophagy initiator Beclin1 during early stages of AD and strategies that have aimed to enhance the degree of autophagy, such as the lentivirusmediated expression of Beclin 1 or the autophagy-inducing blockage of mTor by rapamycin,…”

“, 2018), the degeneration of axons (Kandan et al., 2013), the development of type 2 diabetes mellitus (T2DM), the cerebral desensitization of growth and neurotrophic factors, in particular insulin (Gault and Holscher, 2018; Holscher, 2019), as well as alterations of the dopaminergic system, including the extensive atr…”

“Additionally, the transcription of the biogenesis-mediators PGC1α and mitochondrial nuclear respiratory factor (NRF)1/2 were reduced in the hippocampi of the APPswe/PS1dE9 mice (Pedros et al., 2014).”

“…as exemplified in the previous pages, but also protected endothelial cells of the BBB and neurons from apoptosis in various contexts, leading to the reduced release of the microglial inflammatory activator MMP-3 (Kim et al., 2005; Moon et al., 2009a; Lee J. et al., 2010; Lee et al., 2015).”

“These early impediments in the neuronal insulin and glucose metabolism have been proposed to trigger a detrimental bioenergetic shift from glucose to alternative and less efficient energy substrates (reviewed in Neth and Craft, 2017) and have been suggested to precede any other pathological alteration, including even…”

“…responses, such as a total reduction in naive T-cells, a tendency of T-cells to differentiate into CD4+ subsets or the elevated activity of pro-inflammatory CD4+ Th17 cells (Shalit et al., 1995; Richartz-Salzburger et al., 2007; Speciale et al., 2007; Larbi et al., 2009; Saresella et al., 2011).”

“The NTS, on the other hand, further projects across the entirety of the CNS, ultimately leading to the intestinal return of immune-suppressing signals through the afferent ends of the vagal nerve.”

“AG is also involved in the regulation of the adaptive immune system, which is based on the modulation of T-cells.”

“…in mitochondria-associated genes protect from MPTP oxidative assault in cell and animal models of PD, whereas the deletion of PGC1α exacerbates MPTP-induced injury and excitotoxicity (Scarpulla, 2002, 2006; Kang and Hamasaki, 2005; St.-Pierre et al., 2006; Mudo et al., 2012; Quan et al., 2020).”

“Ghrelin has shown efficacy for the treatment of several mouse models of neurodegenerative disease consistent with the neuroprotective effects of AMPK signaling [208,209].”

“Moreover, ghrelin can enhance several energy metabolic pathways like beta oxidation [133] and alleviate neuronal inflammation by reducing proinflammatory cytokines [134].”

“Other pathologic events include, for example, oxidative stress, mitochondrial damage, dysfunctional autophagy, loss of hippocampal neurogenesis and BBB and microvascular injury (Reich & Holscher, 2020).”

“Most clinical drug trials target at Aβ and tau, but the clinical failures of the recent decades indicate that there are further pathological mechanisms [146].”

“(AD) [80], and Huntington’s disease (HD) [81], all of which have been associated with ghrelin.”

“At present, accumulating studies have identified autophagy as being widely involved in diverse physiological and pathogenetic processes underlying neurodegenerative diseases [13], cancers [14], and metabolic diseases [15].”

“AG also encourages hippocampal neurogenesis and revives cognition in AD (Reich and Hölscher 2020).”

“Therefore, in line with the novel clinical applications suggested for AG in Alzheimer’s and Parkinson’s disease [65], lipodystrophy [66], reproductive toxicity in cancer patients [67] and heart failure [68], serum AG could be considered a sensitive peripheral marker of distinction between NPDR and…”

“Additionally, acylated ghrelin can stimulate the activation of SIRT1 to boost autophagy, which can eliminate harmful proteins [95].”

“Both ghrelin and SCFAs have neuroprotective effects against PD neuropathology [ 70, 71].”

“In recent years, the acylated form of ghrelin has shown protective effects in Alzheimer’s and other neurodegenerative diseases [130], remarkably indicating that the post-translational modification of neuropeptides could be a milestone for their protective effects.”

“This way, while treatment with ghrelin, acylated ghrelin, or synthetic agonists [181,253,256,272] appears advantageous in the long run, the inhibition of BChE [271,273] may provide both long-term and short-term beneficial effects in Alzheimer’s disease.”

“[74, 75].”

“In the contrast, the activation of the ghrelin receptor in immune cells has a positive effect on the suppression of systemic immune responses (Jeon et al., 2019; Reich et al., 2020).”

“Our results showed that ghrelin treatment attenuated the expression of microglial senescence markers and increased Beclin1 and LC3-II levels, indicating improved autophagy-related molecular changes, consistent with its well-known protective effects (Chung et al. 2018; Reich and Holscher 2020).”

“By activating NPY/AgRP neurons in the hypothalamus, it drives feeding behavior and fat storage [73].”

“This indicates its potential as a target for treating neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases [15] .”