<i>INPP5D</i> rs35349669 polymorphism with late-onset Alzheimer's disease: A replication study and meta-analysis

Hua, Jinping; Zhu, Jiajun; Wang, Hui-Fu; Zhang, Wei; Zheng, Zhan-Jie; Kong, Lingli; Tan, Cheng; Wang, Zixuan; Tan, Lin; Tan, Lan

doi:10.18632/oncotarget.12648

Cited by 27 publications

(23 citation statements)

References 20 publications

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“…Although genetic variants in INPP5D have been associated with LOAD risk [5,6,20,21], the role of INPP5D in AD remains unclear. We identified that INPP5D expression levels are increased in the brain of LOAD patients.…”

Section: Discussionmentioning

confidence: 99%

“…Recent large-scale genome-wide association studies (GWAS) reported that many genetic loci associated with LOAD risk are related to inflammatory pathways, suggesting that microglia are involved in modulating AD pathogenesis [3,4]. Among the microglia-related genetic factors in LOAD, a common variant in INPP5D (phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1), rs35349669, confers an increase in LOAD risk (OR=1.08) [4,5]. Conversely, the intronic INPP5D variant rs61068452 is associated with a reduced CSF t-tau/Aβ1-42 ratio, plays a protective role in LOAD (p=1.48E-07) [6].…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, INPP5D inhibits signal transduction initiated by activation of immune cell surface receptors, including Triggering receptor expressed on myeloid cells 2 (TREM2), Fc gamma receptor (Fc R) and Dectin-1 [8]. The conversion of PI (3,4,5)P3 to PI (3,4)P2 is catalyzed by INPP5D following its translocation from the cytosol to the cytoplasmic membrane. The loss of PI (3,4,5)P3 prevents the activation of the immune cell surface receptors [9].…”

Section: Introductionmentioning

confidence: 99%

“…The conversion of PI (3,4,5)P3 to PI (3,4)P2 is catalyzed by INPP5D following its translocation from the cytosol to the cytoplasmic membrane. The loss of PI (3,4,5)P3 prevents the activation of the immune cell surface receptors [9]. Interestingly, genetic variants of TREM2, Fc R, and Dectin-1 are also associated with increased AD risk [10][11][12] and are potentially involved in regulating INPP5D activity.…”

Section: Introductionmentioning

confidence: 99%

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INPP5D Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

Tsai

Lin

Dong

et al. 2020

Preprint

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Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. Methods We performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. Results Differential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. Conclusions Our findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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INPP5D Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

Tsai

Lin

Dong

et al. 2020

Preprint

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“…Spleen tyrosine kinase (SYK) has been shown to play a role in AD pathological lesions, and SYK was therefore considered as a potential drug target for AD 22 . Phosphatidylinositol 3,4,5trisphosphate 5-phosphatase 1 (INPP5D), identified as one of the genetic risk factors for LOAD 23 , affects AD pathology by regulating microglia 24 . Inhibiting tyrosine-protein kinase (HCK) has proved to disturb microglia function and exacerbate neuropathology and neuroinflammation 25 .…”

Section: Discovery Of Disease-associated Microglia Specific Molecularmentioning

confidence: 99%

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

Zhang

Huang

et al. 2020

Preprint

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Systematic identification of molecular networks in disease relevant immune cells of the nervous system is critical for elucidating the underlying pathophysiology of Alzheimer's disease (AD). Two key immune cell types, disease-associated microglia (DAM) and disease-associated astrocytes (DAA), are biologically involved in AD pathobiology. Therefore, uncovering molecular determinants of DAM and DAA will enhance our understanding of AD biology, potentially identifying novel therapeutic targets for AD treatment. Here, we present an integrative, network-based methodology to uncover conserved molecular networks between DAM and DAA. Specifically, we leverage single-cell and single-nucleus RNA sequencing data from both AD transgenic mouse models and AD patient brains, drug-target networks, metabolite-enzyme associations, and the human protein-protein interactome, along with large-scale patient data validation from the MarketScan Medicare Supplemental Database. We find that common and unique molecular network regulators between DAM (i.e, PAK1, MAPK14, and SYK) and DAA (i.e., NFKB1, FOS, and JUN) are significantly enriched by multiple neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1) from genome-wide association studies. Further network analysis reveal shared immune pathways between DAM and DAA, including Fc gamma R-mediated phagocytosis, Th17 cell differentiation, and chemokine signaling. Furthermore, integrative metabolite-enzyme network analyses imply that fatty acids (i.e., elaidic acid) and amino acids (i.e., glutamate, serine, and phenylalanine) may trigger molecular alterations between DAM and DAA. Finally, we prioritize repurposed drug candidates for potential treatment of AD by agents that specifically reverse dysregulated gene expression of DAM or DAA, including an antithrombotic anticoagulant triflusal, a beta2-adrenergic receptor agonist salbutamol, and the steroid medications (fluticasone and mometasone). Individuals taking fluticasone (an approved anti-inflammatory and inhaled corticosteroid) displayed a significantly decreased incidence of AD (hazard ratio (HR) = 0.858, 95% confidence interval [CI] 0.829-0.888, P < 0.0001) in retrospective case-control validation. Furthermore, propensity score matching cohort studies also confirmed an association of mometasone with reduced incidence of AD in comparison to fluticasone (HR =0.921, 95% CI 0.862-0.984, P < 0.0001).

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INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease

Lin

Tsai

Soni

et al. 2022

Alzheimer's & Dementia

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Introduction Inositol polyphosphate‐5‐phosphatase (INPP5D) is a microglia‐enriched lipid phosphatase in the central nervous system. A non‐coding variant (rs35349669) in INPP5D increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear. Methods We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis. Results Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation. Conclusion These data demonstrate that Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.

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INPP5D rs35349669 polymorphism with late-onset Alzheimer's disease: A replication study and meta-analysis

Cited by 27 publications

References 20 publications

INPP5D Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

INPP5D Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease

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INPP5D rs35349669 polymorphism with late-onset Alzheimer's disease: A replication study and meta-analysis

Cited by 27 publications

References 20 publications

INPP5D&nbsp;Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

INPP5D&nbsp;Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease

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Product

Resources

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INPP5D Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia

INPP5D Expression is Associated with Risk for Alzheimer’s Disease and Induced by Plaque-Associated Microglia