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Lack of effect of psychotropic medications on parietal cortical RXFP1 and RXFP3 immunoreactivities in AD. Bar graphs of normalized RXFP1 and RXFP3 immunoreactivities (in arbitrary units) in BA39 of AD who were administered neuroleptics or sedative-hypnotics in the 8 months before death
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Rationale
The G-protein-coupled relaxin family receptors RXFP1 and RXFP3 are widely expressed in the cortex and are involved in stress responses and memory and emotional processing. However, the identification of these receptors in human cortex and their status in Alzheimer’s disease (AD), which is characterized by both cognitive impairments and ne...
Citations
... RLN3-RXFP3 inhibits intracellular cAMP accumulation and activates PKC-dependent ERK1/2 [32]. RLN3-RXFP3 signaling is involved in the metabolic abnormalities observed in patients receiving antipsychotic treatment and in the neurotransmission changes in patients with depression and Alzheimer's disease [33,34]. Additionally, it is involved in regulating hippocampal theta rhythms related to learning and memory, stress response, increased appetite, and arousal [29,[35][36][37]. ...
Relaxin-like peptide family exhibit differential expression patterns in various types of cancers and play a role in cancer development. This family participates in tumorigenic processes encompassing proliferation, migration, invasion, tumor microenvironment, immune microenvironment, and anti-cancer resistance, ultimately influencing patient prognosis. In this review, we explore the mechanisms underlying the interaction between the RLN-like peptide family and tumors and provide an overview of therapeutic approaches utilizing this interaction.
... In parallel with MS1262-reduced noncognitive AD-like neuropsychiatric behaviors such as depression and anxiety (Fig. 3), we identi ed numerous phosphoproteins with MS1262-reversed phosphorylation involved in Relaxin signaling that contains markers of depression in AD 94 (Fig. 5C & S5D). Moreover, MS1262 reinstated gustation pathways whose dysregulation was indicative of impaired sensory systems (e.g., olfactory, visual, auditory, somatosensory, gustatory) and poorer memory in AD 95, 96 because auditory and visual measures were used to detect prodromal AD 97 (Fig. S5D). ...
Current amyloid beta-targeting approaches for Alzheimer’s disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.
... RXfp1, one of the G-protein-coupled relaxin family receptors, is involved in stress responses, memory, and emotional processing. Immunoreactivity of RXfp1 was reduced in the parietal cortex of non-depressed AD patients, but RXfp3 level was upregulated in AD subjects with persistent depression [54]. In contrast, the genes expressed in the hippocampus of Donepezil-administered rats were related to neuroactive ligand-receptor interaction, including Npy2r, Chrm5, Trhr, and Rxfp1 with 2.20, 158, 1.60, and −2.12 FC, respectively. ...
Aster koraiensis Nakai (AK) leaf reportedly ameliorates health problems, such as diabetes. However, the effects of AK on cognitive dysfunction or memory impairment remain unclear. This study investigated whether AK leaf extract could attenuate cognitive impairment. We found that AK extract reduced the production of nitric oxide (NO), tumour necrosis factor (TNF)-α, phosphorylated-tau (p-tau), and the expression of inflammatory proteins in lipopolysaccharide- or amyloid-β-treated cells. AK extract exhibited inhibitory activity of control specific binding on N-methyl-D-aspartate (NMDA) receptors. Scopolamine-induced AD models were used chronically in rats and acutely in mice. Relative to negative controls (NC), hippocampal choline acetyltransferase (ChAT) and B-cell lymphoma 2 (Bcl2) activity was increased in rats chronically treated with scopolamine and fed an AK extract-containing diet. In the Y-maze test, spontaneous alterations were increased in the AK extract-fed groups compared to NC. Rats administered AK extract showed increased escape latency in the passive avoidance test. In the hippocampus of rats fed a high-AK extract diet (AKH), the expression of neuroactive ligand–receptor interaction-related genes, including Npy2r, Htr2c, and Rxfp1, was significantly altered. In the Morris water maze assay of mice acutely treated with scopolamine, the swimming times in the target quadrant of AK extract-treated groups increased significantly to the levels of the Donepezil and normal groups. We used Tg6799 Aβ-overexpressing 5XFAD transgenic mice to investigate Aβ accumulation in animals. In the AD model using 5XFAD, the administration of AK extract decreased amyloid-β (Aβ) accumulation and increased the number of NeuN antibody-reactive cells in the subiculum relative to the control group. In conclusion, AK extract ameliorated memory dysfunction by modulating ChAT activity and Bcl2-related anti-apoptotic pathways, affecting the expression of neuroactive ligand–receptor interaction-related genes and inhibiting Aβ accumulation. Therefore, AK extract could be a functional material improving cognition and memory.
... Further investigation of the functions of this receptor has uncovered that RXFP3 might play a vital role in several aging-related disorders, as a connection has been found to several hallmarks of aging, such as oxidative stress and DNA damage response [24], similarly to the aging keystone GIT2 [6,7]. In addition, research by other groups has elucidated possible roles for RXFP3 in stress responses [25], anxiety [26], depression [26,27], feeding [15,[28][29][30], arousal [28], and alcohol addiction [31]. Given the plethora of possible physiological activities of RXFP3, we will next assess how RXFP3 functionality may intersect with several of the classical hallmark processes involved with the aging process ( Figure 1). ...
... Alzheimer's disease is primarily represented as a dysfunctional capacity for short-term memory formation and then, at a later stage, a dysfunction in long-term memory recollection. It is relevant to note that depletion of RXFP3 levels in the brain have been associated with long-term memory regulation in adult mice [27]. In addition to long-term memory recall, RXFP3 functionality has also been associated with spatial memory formation [148,149]. ...
During the aging process our body becomes less well equipped to deal with cellular stress, resulting in an increase in unrepaired damage. This causes varying degrees of impaired functionality and an increased risk of mortality. One of the most effective anti-aging strategies involves interventions that combine simultaneous glucometabolic support with augmented DNA damage protection/repair. Thus, it seems prudent to develop therapeutic strategies that target this combinatorial approach. Studies have shown that the ADP-ribosylation factor (ARF) GTPase activating protein GIT2 (GIT2) acts as a keystone protein in the aging process. GIT2 can control both DNA repair and glucose metabolism. Through in vivo co-regulation analyses it was found that GIT2 forms a close coexpression-based relationship with the relaxin-3 receptor (RXFP3). Cellular RXFP3 expression is directly affected by DNA damage and oxidative stress. Overexpression or stimulation of this receptor, by its endogenous ligand relaxin 3 (RLN3), can regulate the DNA damage response and repair processes. Interestingly, RLN3 is an insulin-like peptide and has been shown to control multiple disease processes linked to aging mechanisms, e.g., anxiety, depression, memory dysfunction, appetite, and anti-apoptotic mechanisms. Here we discuss the molecular mechanisms underlying the various roles of RXFP3/RLN3 signaling in aging and age-related disorders.
... RXFP3 has been implicated in stress response [21], anxiety [22], depression [22,23], feeding [24][25][26][27], arousal [24] and alcohol addiction [28] using RXFP3/RLN3 deficient mouse models. The first indications linking the RXFP3/RLN3 system to stress and metabolic control, was through its presence in the hypothalamic regions involved in the hypothalamicpituitary-adrenal axis [27,[29][30][31] and the paraventricular nucleus [26,27]. ...
DNA damage response (DDR) processes, often caused by oxidative stress, are important in aging and -related disorders. We recently showed that G protein-coupled receptor (GPCR) kinase interacting protein 2 (GIT2) plays a key role in both DNA damage and oxidative stress. Multiple tissue analyses in GIT2KO mice demonstrated that GIT2 expression affects the GPCR relaxin family peptide 3 receptor (RXFP3), and is thus a therapeutically-targetable system. RXFP3 and GIT2 play similar roles in metabolic aging processes. Gaining a detailed understanding of the RXFP3-GIT2 functional relationship could aid the development of novel anti-aging therapies. We determined the connection between RXFP3 and GIT2 by investigating the role of RXFP3 in oxidative stress and DDR. Analyzing the effects of oxidizing (H2O2) and DNA-damaging (camptothecin) stressors on the interacting partners of RXFP3 using Affinity Purification-Mass Spectrometry, we found multiple proteins linked to DDR and cell cycle control. RXFP3 expression increased in response to DNA damage, overexpression, and Relaxin 3-mediated stimulation of RXFP3 reduced phosphorylation of DNA damage marker H2AX, and repair protein BRCA1, moderating DNA damage. Our data suggests an RXFP3-GIT2 system that could regulate cellular degradation after DNA damage, and could be a novel mechanism for mitigating the rate of age-related damage accumulation.
... Also with respect to migraine is ITGB3 which was shown to influence serotonin blood levels, serotonin being previously implicated in migraine etiology [48,49]. Dementia and AD potential markers are present in panel II, RXFP1, RELN, EGF and the previously mentioned LRP1 [50,51]. TBI and dementia associations were previously demonstrated [16,22]. ...
Traumatic Brain Injury (TBI) and persistent post-concussion syndrome (PCS) including chronic migraine (CM) are major health issues for civilians and the military. It is important to understand underlying biochemical mechanisms of these conditions, and be able to monitor them in an accurate and minimally invasive manner. This study describes the initial use of a novel serum analytical platform to help distinguish TBI patients, including those with post-traumatic headache (PTH), and to help identify phenotypes at play in these disorders. The hypothesis is that physiological responses to disease states like TBI and PTH and related bodily stresses are reflected in biomolecules in the blood in disease-specific manner. Leave one out (serum sample) cross validations (LOOCV) and sample randomizations were utilized to distinguished serum samples from the following TBI patient groups: TBI +PTSD + CM + severe depression (TBI “most affected” group) vs healthy controls, TBI “most affected” vs TBI, TBI vs controls, TBI + CM vs controls, and TBI + CM vs TBI. Inter-group discriminatory p values were ≤ 10⁻¹⁰, and sample group randomizations resulted in p non-significant values. Peptide/protein identifications of discriminatory mass peaks from the TBI “most affected” vs controls and from the TBI plus vs TBI minus CM groups yielded information of the cellular/molecular effects of these disorders (immune responses, amyloidosis/Alzheimer’s disease/dementia, neuronal development). More specific biochemical disease effects appear to involve blood brain barrier, depression, migraine headache, autoimmunity, and autophagy pathways. This study demonstrated the ability for the first time of a novel, accurate, biomarker platform to monitor these conditions in serum, and help identify biochemical relationships leading to better understanding of these disorders and to potential therapeutic approaches.
... In a recent study of the neocortex of patients with Alzheimer's disease (AD) and their age-matched controls, we have found that alterations in the levels of RXFP1 and RXFP3 receptors were more closely associated with depressive symptoms than with cognitive decline or Aβ42 levels (Lee et al., 2016). While RXFP3 receptor-like immunoreactivity in the parietal cortex was up-regulated in depressed AD patients and unchanged in non-depressed AD patients, RXFP1 receptor-like immunoreactivity in the parietal cortex was unchanged in depressed AD patients and downregulated in non-depressed AD patients (Lee et al., 2016). ...
... In a recent study of the neocortex of patients with Alzheimer's disease (AD) and their age-matched controls, we have found that alterations in the levels of RXFP1 and RXFP3 receptors were more closely associated with depressive symptoms than with cognitive decline or Aβ42 levels (Lee et al., 2016). While RXFP3 receptor-like immunoreactivity in the parietal cortex was up-regulated in depressed AD patients and unchanged in non-depressed AD patients, RXFP1 receptor-like immunoreactivity in the parietal cortex was unchanged in depressed AD patients and downregulated in non-depressed AD patients (Lee et al., 2016). Neuropsychiatric conditions such as depression, anxiety and psychosis in AD patients (also known as 'behavioural and psychological symptoms of dementia') are thought to arise from degeneration of monoaminergic neurons and accompanying perturbations in neurotransmission (Francis et al., 2010;Ramirez et al., 2014). ...
... Previous reports suggest that dysregulation of the HPA axis in AD could underlie neuropsychiatric behaviours (Notarianni, 2013;Lucassen et al., 2014). Exogenous relaxin-3 altered activity of the HPA axis and it is possible that changes in endogenous relaxin-3/RXFP3 receptor signalling contribute to altered HPA axis functioning and adaptive plasticity in AD (Lee et al., 2016), although further studies are required to understand this relationship and confirm its existence in human brain. ...
Relaxin‐3 has been proposed to modulate emotional–behavioural functions such as arousal and behavioural activation, appetite regulation, stress responses, anxiety, memory, sleep and circadian rhythm. The nucleus incertus (NI), in the midline tegmentum close to the fourth ventricle, projects widely throughout the brain and is the primary site of relaxin‐3 neurons. Over recent years, a number of preclinical studies have explored the function of the NI and relaxin‐3 signalling, including reports of mRNA or peptide expression changes in the NI in response to behavioural or pharmacological manipulations, effects of lesions or electrical or pharmacological manipulations of the NI, effects of central microinfusions of relaxin‐3 or related agonist or antagonist ligands on physiology and behaviour, and the impact of relaxin‐3 gene deletion or knockdown. Although these individual studies reveal facets of the likely functional relevance of the NI and relaxin‐3 systems for human physiology and behaviour, the differences observed in responses between species (e.g. rat vs. mouse), the clearly identified heterogeneity of NI neurons and procedural differences between laboratories are some of the factors that have prevented a precise understanding of their function. This review aims to draw attention to the current preclinical evidence available that suggests the relevance of the NI/relaxin‐3 system to the pathology and/or symptoms of certain neuropsychiatric disorders and to provide cognizant directions for future research to effectively and efficiently uncover its therapeutic potential.
Linked Articles
This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc
Current amyloid beta-targeting approaches for Alzheimer’s disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.
One-Sentence Summary
A brain-penetrant inhibitor of G9a methylase blocks G9a translational mechanism to reverse Alzheimer’s disease related proteome for effective therapy.
While numerous single nucleotide variants and small indels have been identified in Parkinson’s disease (PD), the genome-wide contribution of structural variants (SVs), copy number variants (CNVs) and short tandem repeats (STRs) remains poorly understood. Here we investigated the association between these variants and PD using the high-depth whole-genome sequencing data from 466 PD patients and 513 healthy elderlies. A total of 29,561 SVs, 32,153 CNVs and 174,905 STRs were detected. Overall, CNV deletions were significantly enriched in the end-proportion of autosomal chromosomes in PD. Genome-wide association study identified 11 novel signals (1 SV, 4 CNVs and 6 STRs) reaching genome-wide significance. Among these, the deletion nearby MUC19 and the 5-copy GGGAAA repeat in SLC2A13 reduced the penetrance of LRRK2 G2385R variant. Moreover, genes with these variants were specifically expressed in dopaminergic neurons and highly dosage-sensitive. These data provided novel insights into the genetic architecture of PD.
The relaxin-3/RXFP3 system is one of several neuropeptidergic systems putatively implicated in regulating the behavioural alterations that characterise clinical depression and anxiety, making it a potential target for clinical translation. Accordingly, this systematic review identified published reports on the role of relaxin-3/RXFP3 signalling in these neuropsychiatric disorders and their behavioural endophenotypes, evaluating evidence from animal and human studies to ascertain any relationship. We searched PubMed, EMBASE, PsycINFO and Google Scholar databases up to February 2021, finding 609 relevant records. After stringent screening, 51 of these studies were included in the final synthesis. There was considerable heterogeneity in study designs and some inconsistency across study outcomes. However, experimental evidence is consistent with an ability of relaxin-3/RXFP3 signalling to promote arousal and suppress depressive- and anxiety-like behaviour. Moreover, meta-analyses of six to eight articles investigating food intake revealed that acute RXFP3 activation had strong orexigenic effects in rats. This appraisal also identified the lack of high-quality clinical studies pertinent to the relaxin-3/RXFP3 system, a gap that future research should attempt to bridge.
