The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer’s disease

Moutinho, Miguel; Puntambekar, Shweta S.; Tsai, Andy Po‐Yi; Coronel, Israel; Lin, Peter Bor‐Chian; Casali, Brad T.; Martínez, Paula; Oblak, Adrian L.; Lasagna‐Reeves, Cristian A.; Lamb, Bruce T.; Landreth, Gary E.

doi:10.1126/scitranslmed.abl7634

Cited by 48 publications

(50 citation statements)

References 82 publications

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“…The copyright holder for this preprint this version posted September 22, 2022. ; https://doi.org/10.1101/2022.09.20.508759 doi: bioRxiv preprint amyloid pathology and neuronal dystrophy in AD 90 . Notably, the top-ranked metabolites of GP183 and C3AR are both coproporphyrin III.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, HCAR2 (GPR109A), a microglia receptor that was induced by amyloid pathology in AD 89 , was also identified as being agonized by the metabolite nicotinic acid derived from R. guavus 7 . A FDA-approved drug Niaspan was reported to activate HCAR2 to modulate amyloid pathology and neuronal dystrophy in AD 90 . Notably, the top-ranked metabolites of GP183 and C3AR are both coproporphyrin III.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Qiu

Hou

Zhou

et al. 2022

Preprint

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Accumulating evidence suggests that gut-microbiota metabolites contribute to human disease pathophysiology, yet the host receptors that sense these metabolites are largely unknown. Here, we developed a systems pharmacogenomics framework that integrates machine learning (ML), AlphaFold2-derived structural pharmacology, and multi-omics to identify disease-relevant metabolites derived from gut-microbiota with non-olfactory G-protein-coupled receptors (GPCRome). Specifically, we evaluated 1.68 million metabolite-protein pairs connecting 408 human GPCRs and 516 gut metabolites using an Extra Trees algorithm-improved structural pharmacology strategy. Using genetics-derived Mendelian randomization and multi-omics (including transcriptomic and proteomic) analyses, we identified likely causal GPCR targets (C3AR, FPR1, GALR1 and TAS2R60) in Alzheimer's disease (AD). Using three-dimensional structural fingerprint analysis of the metabolite-GPCR complexome, we identified over 60% of the allosteric pockets of orphan GPCR models for gut metabolites in the GPCRome, including AD-related orphan GPCRs (GPR27, GPR34, and GPR84). We additionally identified the potential targets (e.g., C3AR) of two AD-related metabolites (3-hydroxybutyric acid and Indole-3-pyruvic acid) and four metabolites from AD-related bacterium Eubacterium rectale, and also showed that tridecylic acid is a candidate ligand for orphan GPR84 in AD. In summary, this study presents a systems pharmacogenomics approach that serves to uncover the GPCR molecular targets of gut microbiota in AD and likely many other human diseases if broadly applied.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Qiu

Hou

Zhou

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Genetic deletion of HCAR2 markedly impaired the uptake of Aβ deposition by microglia, leading to an increase in Aβ deposition and cognitive functional impairment in 5xFAD mice. Interestingly, activation of HCAR2 by using an FDA-approved formulation of niacin (Niaspan) reduced Aβ deposition and neuronal loss, resulting in improved cognitive function in 5xFAD mice ( Moutinho et al, 2022 ), suggesting that HCAR2 activity is required for the effective clearance of Aβ deposition during the early-onset of AD.…”

Section: Microglia-related Risk Factors For Late-onset Alzheimer’s Di...mentioning

confidence: 99%

Functional and Phenotypic Diversity of Microglia: Implication for Microglia-Based Therapies for Alzheimer’s Disease

Eddie

2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is closely associated with the accumulation of β-amyloid (Aβ) and neurofibrillary tangles (NFTs). Apart from Aβ and NFT pathologies, AD patients also exhibit a widespread microglial activation in various brain regions with elevated production of pro-inflammatory cytokines, a phenomenon known as neuroinflammation. In healthy central nervous system, microglia adopt ramified, “surveying” phenotype with compact cell bodies and elongated processes. In AD, the presence of pathogenic proteins such as extracellular Aβ plaques and hyperphosphorylated tau, induce the transformation of ramified microglia into amoeboid microglia. Ameboid microglia are highly phagocytic immune cells and actively secrete a cascade of pro-inflammatory cytokines and chemokines. However, the phagocytic ability of microglia gradually declines with age, and thus the clearance of pathogenic proteins becomes highly ineffective, leading to the accumulation of Aβ plaques and hyperphosphorylated tau in the aging brain. The accumulation of pathogenic proteins further augments the neuroinflammatory responses and sustains the activation of microglia. The excessive production of pro-inflammatory cytokines induces a massive loss of functional synapses and neurons, further worsening the disease condition of AD. More recently, the identification of a subset of microglia by transcriptomic studies, namely disease-associated microglia (DAM), the progressive transition from homeostatic microglia to DAM is TREM2-dependent and the homeostatic microglia gradually acquire the state of DAM during the disease progression of AD. Recent in-depth transcriptomic analysis identifies ApoE and Trem2 from microglia as the major risk factors for AD pathogenesis. In this review, we summarize current understandings of the functional roles of age-dependent microglial activation and neuroinflammation in the pathogenesis of AD. To this end, the exponential growth in transcriptomic data provides a solid foundation for in silico drug screening and gains further insight into the development of microglia-based therapeutic interventions for AD.

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“…Working memory in mice was assessed by spontaneous alternation in the Y-maze task as previously described (Moutinho et al, 2022). Animals were placed in the Y-maze with free access to all three arms and tracked and recorded for 8 min using ANY-maze software (Stoelting Co.).…”

Section: Y-maze Taskmentioning

confidence: 99%

Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

Tsai

Dong

Lin

et al. 2022

Preprint

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Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimers disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and acts in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2 P522R variant, is a mild hypermorph that attenuates AD risk. We report the identification of a PLCG2 variant, PLCG2 M28L variant, associated with loss-of-function and confers increased AD risk. PLCG2 P522R variant attenuates disease in an amyloidogenic murine AD model, whereas PLCG2 M28L variant exacerbates the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2 M28L variant as a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

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The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer’s disease

Cited by 48 publications

References 82 publications

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

Functional and Phenotypic Diversity of Microglia: Implication for Microglia-Based Therapies for Alzheimer’s Disease

Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

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