Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer′s disease

Tian, Jing; Guo, Lan; Sui, Shaomei; Driskill, Christopher; Phensy, Aarron; Wang, Qi; Gauba, Esha; Zigman, Jeffrey M.; Swerdlow, Russell H.; Kroener, Sven; Du, Heng

doi:10.1126/scitranslmed.aav6278

Cited by 52 publications

(52 citation statements)

References 76 publications

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“…Most importantly, it is been proven that Aβ combines with GHSR1α, preventing activation of GHSR1α and GHSR1α/DRD1 heterodimerization. The resultant reduced GHSR1α/DRD1 interaction contributes to hippocampal synaptic injury, leading to memory damage (101).…”

Section: Aβ Interact With Hippocampal Ghrelin/ghsr1α Signaling In Admentioning

confidence: 99%

“…These results may reflect the insensitivity of GHSR1α to activators in AD patients. Furthermore, it has been shown that the combined activation of GHSR1α and DRD1 with their selective agonists MK0677 and SKF81297, respectively, rescues hippocampal synaptic function and cognition from Aβ toxicity in young 5XFAD mice (101). However, whether MK0677/SKF81297 is beneficial for older 5XFAD mice requires further investigation.…”

Section: Aβ Interact With Hippocampal Ghrelin/ghsr1α Signaling In Admentioning

confidence: 99%

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New Insights Into the Pathogenesis of Alzheimer's Disease

et al. 2020

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Alzheimer's disease (AD), a common neurodegenerative disease in the elderly and the most prevalent cause of dementia, is characterized by progressive cognitive impairment. The prevalence of AD continues to increase worldwide, becoming a great healthcare challenge of the twenty-first century. In the more than 110 years since AD was discovered, many related pathogenic mechanisms have been proposed, and the most recognized hypotheses are the amyloid and tau hypotheses. However, almost all clinical trials targeting these mechanisms have not identified any effective methods to treat AD. Scientists are gradually moving away from the simple assumption, as proposed in the original amyloid hypothesis, to new theories of pathogenesis, including gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. To place these findings in context, we first reviewed the neuropathology of AD and further discussed new insights in the pathogenesis of AD.

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Section: Aβ Interact With Hippocampal Ghrelin/ghsr1α Signaling In Admentioning

confidence: 99%

Section: Aβ Interact With Hippocampal Ghrelin/ghsr1α Signaling In Admentioning

confidence: 99%

New Insights Into the Pathogenesis of Alzheimer's Disease

et al. 2020

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“…This observation, together with the ineffectiveness of MK0677 as seen in our study and a previous clinical trial [19], seems to suggest a suppressed GHSR1α response to its ligand-or agonist-induced activation in AD-relevant pathophysiological settings. Indeed, we have determined that complexation with Aβ inhibits ligand-induced activation of GHSR1α and thus suppresses GHSR1α's regulation of dopamine receptor D1 (DRD1), leading to hippocampal synaptic deficits [60]. We therefore form a "ghrelin resistance" hypothesis of AD hippocampal synaptic failure.…”

Section: Discussionmentioning

confidence: 98%

MK0677, a Ghrelin Mimetic, Improves Neurogenesis but Fails to Prevent Hippocampal Lesions in a Mouse Model of Alzheimer’s Disease Pathology

Tian

Wang

et al. 2019

JAD

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Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer's disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-β (Aβ) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3 mg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aβ toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment.

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“…As previously mentioned, AKAP5 is a gene related to synaptic plasticity and memory and is part of a LncACeNET in AD [ 96 ]. As for DRD1, it is a dopamine receptor whose dysregulation could contribute to synaptic injury in AD [ 158 ].…”

Section: Cerna Network and Neurodegenerative Diseasesmentioning

confidence: 99%

Competing Endogenous RNA Networks as Biomarkers in Neurodegenerative Diseases

Moreno-García

López-Royo

Calvo

et al. 2020

IJMS

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Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration of RNA metabolism is a key factor in the etiopathogenesis of these complex disorders. Non-coding RNAs are the major contributor to the human transcriptome and are particularly abundant in the central nervous system, where they have been proposed to be involved in the onset and development of NDDs. Interestingly, some ncRNAs (such as lncRNAs, circRNAs and pseudogenes) share a common functionality in their ability to regulate gene expression by modulating miRNAs in a phenomenon known as the competing endogenous RNA mechanism. Moreover, ncRNAs are found in body fluids where their presence and concentration could serve as potential non-invasive biomarkers of NDDs. In this review, we summarize the ceRNA networks described in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis and spinocerebellar ataxia type 7, and discuss their potential as biomarkers of these NDDs. Although numerous studies have been carried out, further research is needed to validate these complex interactions between RNAs and the alterations in RNA editing that could provide specific ceRNET profiles for neurodegenerative disorders, paving the way to a better understanding of these diseases.

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Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer′s disease

Cited by 52 publications

References 76 publications

New Insights Into the Pathogenesis of Alzheimer's Disease

New Insights Into the Pathogenesis of Alzheimer's Disease

MK0677, a Ghrelin Mimetic, Improves Neurogenesis but Fails to Prevent Hippocampal Lesions in a Mouse Model of Alzheimer’s Disease Pathology

Competing Endogenous RNA Networks as Biomarkers in Neurodegenerative Diseases

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