Gpr158 mediates osteocalcin’s regulation of cognition

Khrimian, Lori; Obri, Arnaud; Ramos-Brossier, Mariana; Rousseaud, Audrey; Moriceau, Stéphanie; Nicot, Anne-Sophie; Mera, Paula; Kosmidis, Stylianos; Karnavas, Theodoros; Saudou, Frédéric; Gao, Xiao‐Bing; Oury, Franck; Kandel, Eric R.; Karsenty, G.

doi:10.1084/jem.20171320

Cited by 228 publications

(314 citation statements)

References 32 publications

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“…As expected, the only phenotype that could not be recapitulated in mice lacking Osteocalcin only postnatally was developmental, i.e. their hypomorphic hippocampi 15 .…”

Section: Osteocalcin's Regulation Of Anxiety and Cognition In Adult Micesupporting

confidence: 75%

“…Vehicle- and osteocalcin-treated were analyzed when they were 12-or 16-month-old. What was observed is that chronic delivery of uncarboxylated osteocalcin in 10-or 14-month-old mice fully rescued their deficit in cognitive function and decreased their anxiety-like behavior 15 .…”

Section: Osteocalcin Is Necessary and Sufficient To Correct Age-relatmentioning

confidence: 91%

“…That this spiked plasma could improve cognitive function and decrease anxiety-like behavior in older WT mice to the same extend as plasma from young WT mice, was a strong indication that osteocalcin was not only necessary but also sufficient to improve cognitive function and to hamper anxiety-like behavior in adult mice. In a mirror image experiment, depleting every form of osteocalcin from the plasma of young WT mice though immunological means, removed from WT plasma its ability to improve cognitive functions and to decrease anxiety-like behavior 15 (Figure 4b). …”

Section: Osteocalcin Is Necessary and Sufficient To Correct Age-relatmentioning

confidence: 99%

“…Yet this function of osteocalcin is of fundamental importance to link this hormone, or its lack thereof, to the biology of aging. The first reason to write a review on this topic at the present time is that the biomedical importance of osteocalcin's regulation of several behaviors was recently underscored and linked to the aging of the brain 15 . A second reason is that major progress has recently been made in the elucidation of the molecular basis of osteocalcin's functions in the brain.…”

Section: Introductionmentioning

confidence: 99%

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Osteocalcin in the brain: from embryonic development to age-related decline in cognition

et al. 2018

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A remarkable, totally unexpected aspect of the bone-derived hormone osteocalcin is that it is necessary for both brain development and brain function in the mouse since its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behavior. The regulation of cognitive function by osteocalcin, together with the fact its circulating levels decrease in midlife compared to adolescence in all species tested raised the prospect that osteocalcin may be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this review, recent data indicate that this is indeed the case and that osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young WT mice. The diversity and amplitude of the functions of osteocalcin in the brain during development and postnatally had long called for the identification of its receptor in the brain, which was also recently achieved. This review presents our current understanding of osteocalcin's biology in the brain, highlighting the bony-vertebrate specificity of the regulation of cognitive function, and pointing toward where therapeutic opportunities may exist.

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“…As expected, the only phenotype that could not be recapitulated in mice lacking Osteocalcin only postnatally was developmental, i.e. their hypomorphic hippocampi 15 .…”

Section: Osteocalcin's Regulation Of Anxiety and Cognition In Adult Micesupporting

confidence: 75%

Section: Osteocalcin Is Necessary and Sufficient To Correct Age-relatmentioning

confidence: 91%

Section: Osteocalcin Is Necessary and Sufficient To Correct Age-relatmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Osteocalcin in the brain: from embryonic development to age-related decline in cognition

et al. 2018

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“…Impaired GDNF function has been shown at gene and protein level to occur in diverticular disease and during early stages of diverticula formation 31. Plausible links to neuronal physiology are also evident for GPR158 , a G-protein coupled orphan receptor32 and brain-derived neurotropic factor.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer¹,

Harrison²,

Buch³

et al. 2019

Gut

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ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

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Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study

et al. 2019

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IMPORTANCE Young mouse plasma restores memory in aged mice, but, to our knowledge, the effects are unknown in patients with Alzheimer disease (AD). OBJECTIVE To assess the safety, tolerability, and feasibility of infusions of young fresh frozen plasma (yFFP) from donors age 18 to 30 years in patients with AD. DESIGN, SETTING, AND PARTICIPANTS The Plasma for Alzheimer Symptom Amelioration (PLASMA) study randomized 9 patients under a double-blind crossover protocol to receive 4 once-weekly infusions of either 1 unit (approximately 250 mL) of yFFP from male donors or 250 mL of saline, followed by a 6-week washout and crossover to 4 once-weekly infusions of an alternate treatment. Patients and informants were masked to treatment and subjective measurements. After an open-label amendment, 9 patients received 4 weekly yFFP infusions only and their subjective measurements were unmasked. Patients were enrolled solely at Stanford University, a tertiary academic medical center, from September 2014 to December 2016, when enrollment reached its target. Eighteen consecutive patients with probable mild to moderate AD 1 dementia, a Mini-Mental State Examination (score of 12 to 24 inclusive), and an age of 50 to 90 years were enrolled. Thirty-one patients were screened and 13 were excluded: 11 failed the inclusion criteria and 2 declined to participate. INTERVENTIONS One unit of yFFP from male donors/placebo infused once weekly for 4 weeks. MAIN OUTCOME AND MEASURES The primary outcomes were the safety, tolerability, and feasibility of 4 weekly yFFP infusions. Safety end point analyses included all patients who received the study drug/placebo. RESULTS There was no difference in the age (mean [SD], 74.17 [7.96] years), sex (12 women [67%]), or baseline Mini-Mental State Examination score (mean [SD], 19.39 [3.24]) between the crossover (n = 9) and open-label groups (n = 9). There were no related serious adverse events. One patient discontinued participation because of urticaria and another because of an unrelated stroke. There was no statistically significant difference between the plasma (17 [94.4%]) and placebo (9 [100.0%]) cohorts for other adverse events, which were mild to moderate in severity. The most common adverse events in the plasma group included hypertension (3 [16.7%]), dizziness (2 [11.1%]), sinus bradycardia (3 [16.7%]), headache (3 [16.7%]), and sinus tachycardia (3 [16.7%]). The mean visit adherence (n = 18) was 86% (interquartile range, 87%-100%) and adherence, accounting for a reduction in the total visit requirement due to early patient discontinuation, was 96% (interquartile range, 89%-100%). CONCLUSIONS AND RELEVANCE The yFFP treatment was safe, well tolerated, and feasible. The study's limitations were the small sample size, short duration, and change in study design. The results warrant further exploration in larger, double-blinded placebo-controlled clinical trials.

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Gpr158 mediates osteocalcin’s regulation of cognition

Cited by 228 publications

References 32 publications

Osteocalcin in the brain: from embryonic development to age-related decline in cognition

Osteocalcin in the brain: from embryonic development to age-related decline in cognition

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study

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