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.
Highlights
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are multi-faceted neurodegenerative diseases that reach far beyond the accumulation and aggregation of Amyloid Beta (Aß), Tau and Alpha (α)-synuclein
The last decades of research have indicated that cognitive decline is driven by the interplay of various pathologic processes, involving insulin-associated bioenergetic impairments and the reduced cerebral metabolization of glucose (Neth and Craft, 2017), mitochondrial defects (Bose and Beal, 2016; Onyango et al, 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, 2017; Fujikake et al, 2018; Liu J. et al, 2019), oxidative stress (Cenini et al, 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, 2019; Stancu et al, 2019), demyelination
This suggests that multiple pathologic, and protective, factors cooperate in the progression of AD and that that a differential treatment regimen, which commonly necessitates the use of multiple drugs for chronically advancing disorders, might be necessary for individual patients
Summary
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are multi-faceted neurodegenerative diseases that reach far beyond the accumulation and aggregation of Amyloid Beta (Aß), Tau and Alpha (α)-synuclein. Cell and animal studies in AD models as well as post-mortem examinations of patients, not always matching perfectly, signify that the transcription of fusion-enhancers (OPA1, mitofusin (Mfn)1/2) is attenuated and the expression or activity of fissionmodulators (dynamin-related protein 1 (Drp1), mitochondrial fission 1 protein (Fis1) and S-nitrosylated Fis1) are aberrantly elevated These alterations provoked mitochondrial hyperfission, neuronal injury and synaptic degeneration in vitro and in vivo (Wang et al, 2008, 2009; Cho et al, 2009). Immunohistological investigations in the brain tissue of AD patients suggest that early increases in the neuronal rate of autophagy compensate for the accumulation of waste products, whereas the lysosomal function (proteolytic enzyme activity) and the clearance of lysosomal vacuoles is gradually impaired 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). 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 atrophy and cognitive impediments (Fang et al, 2019; Liu J. et al, 2019)
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