Your doctors and stroke hospital should contact researchers and get appropriate human research going. Not doing so is an indictment of the complete stroke hospital starting at the top with the board of directors.
Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer’s disease
Molecular Neurodegeneration volume 16, Article number: 23 (2021)
Abstract
Background
Recently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer’s disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD.
Methods
We used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo−/−) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses.
Results
Our in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo−/− mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo−/− mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism.
Conclusion
Our findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases.
Background
Neurodegenerative disorders have become one of the greatest challenges and threats to our society because the incidence of these diseases is high in the middle-age and elderly populations. Despite the huge advancement in the health sciences, no therapeutics are available for most neurodegenerative diseases [1, 2]. Currently, the most important and debilitating neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). In all these neurodegenerative diseases, AD is a prime focus for researchers and clinicians, as recent statistical data on AD reported that globally, more than 50 million individuals are affected with AD, and this number will triple by 2050. The worldwide cost of AD is approximately one trillion dollars annually, which will reach two trillion by the year 2030 [3]. Therefore, it is of the utmost importance to reveal the underlying mechanisms and explore potential novel therapeutic targets/agents for the treatment of AD. Recently, researchers have shown great interest in brain metabolic disorders in neurodegenerative diseases, and studies have suggested that aberrant brain metabolism plays a role in the disease-modifying effects of effective therapeutic substances against neurodegenerative diseases such as AD [4, 5]. Several established studies have reported that impaired insulin activities and neuronal insulin resistance are associated with AD pathologies, while regulation of these factors prevents AD [6,7,8,9,10]. Among brain metabolic perturbations that regulate neuronal insulin resistance and insulin signaling, the signaling of adiponectin and its receptor are among the most recent and indispensable research areas. These signaling pathways have been altered in the brain and implicated in metabolic-associated neurological disorders, and they may be a contributing risk factor for AD and other neurodegenerative diseases. Subjects with adiponectin deficiency developed insulin resistance in the brain and impaired downstream insulin signaling, leading to AD pathology. Adiponectin has been reported to function as an anti-diabetic, insulin-sensitizing, anti-inflammatory and antioxidant agent and to provide protection against metabolic-associated AD [11,12,13,14,15,16]. Waragai et al reported the reduction of adiponectin in AD patients and suggested that reduced adiponectin signaling is involved in AD [17]. Importantly, adiponectin signaling through AdipoR1 has beneficial effects on brain metabolism via AMP-activated protein kinase (AMPK) activation and is consequently implicated in the regulation of energy balance and metabolism as well as multiple other functions, including sensitization of the insulin receptor signaling pathway, stimulation of mitochondria biogenesis, and suppression of inflammation [18,19,20,21,22]. Hence, adiponectin is an interesting endogenous therapeutic candidate for the prevention of metabolic-associated neurodegenerative diseases such as AD [14,15,16, 23], and future studies should investigate mimetics of adiponectin that will also act as adiponectin receptor agonists because the conversion of full-length adiponectin into an effective drug is limited due to its size. However, there have been several recent reports that the adiponectin paradox associated with other chronic diseases might be involved in the pathogenesis of AD. In other experimental approaches and studies, adiponectin has been shown to be detrimental in conditions such as chronic heart and chronic kidney diseases, which gives rise to the adiponectin paradox [24,25,26,27,28]. Recently, epidemiological and research studies have shown that high serum levels of adiponectin are associated with low skeletal muscle mass, low muscle density, and poor physical functioning, which are ultimately implicated in disability and mortality [29,30,31]. In contrast, in the brain, adiponectin is protective against central nervous system (CNS)-neurotoxic agents and conditions such as 1-methyl-4-phenyl-pyridinium (MPP+), kainic acid acid-induced excitotoxicity, in vitro amyloid beta (Aβ)-induced toxicity and synuclein-induced neurodegeneration [22, 32,33,34,35]. Adiponectin reduces Aβ oligomer (AβO)-mediated neuroinflammation [36]. Additionally, our group discovered the biological and therapeutic effects of osmotin, a plant protein and homologue of adiponectin [37, 38]. Osmotin was protective in Aβ and transgenic AD mouse models [37,38,39,40]. We also confirmed that osmotin acts as an anti-inflammatory, anti-diabetic and anti-obesity agent [41, 42]. Therefore, adiponectin-based mimetic therapeutic approaches should be closely investigated for all relevant conditions and experimental systems. Of note, we aimed to test the therapeutic effect of an adiponectin-mimetic nonapeptide (C-T-Q-G-P-C-G-P-T (Os-pep)) in early-stage AD mouse models as well as in adiponectin-deficient mice, which is a model that was recently found to show AD pathology.
Several ligands for adiponectin receptors have been reported, including osmotin, which reduces AD pathology [16, 37,38,39,40,41]. However, osmotin has faced the same problems and limitations as adiponectin; due to its large size, osmotin has been limited in its efficacy in translational studies. Therefore, as a translational strategy, we extended the research approach by utilizing the osmotin-based small adiponectin-mimetic Os-pep, which is a very structurally stable peptide that interacts with the adiponectin recognition site on AdipoR1 and shows similar activity as adiponectin and osmotin [37, 43,44,45]. Considering the evidence that Os-pep mimics adiponectin, Os-pep may also have significant potential therapeutic value for the prevention of metabolic-associated AD. It has been recently reported that aberrant adiponectin and AdipoR1/AMPK signaling are associated with impaired insulin signaling and brain insulin resistance in AD-associated pathology [14,15,16]. Furthermore, recent studies have highlighted the mechanistic and potential therapeutic effects of adiponectin and adiporon, which are stimulators of adiponectin receptors, on AD through the activation of metabolic cascades such as the AdipoR1/AMPK and downstream insulin signaling pathways [14,15,16,17, 22]. Herein, we hypothesize that novel Os-pep acts as an adiponectin-mimetic peptide to activate AdipoR1/AMPK signaling and subsequently rescue aberrant neuronal metabolism by reducing neuronal insulin resistance and activating downstream insulin signaling, which leads to improvements in synaptic and memory functions in AD and adiponectin knockout (Adipo−/−) mice.
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