INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia

Tsai, Andy Po‐Yi; Lin, Peter Bor‐Chian; Dong, Chuanpeng; Moutinho, Miguel; Casali, Brad T.; Liu, Yunlong; Lamb, Bruce T.; Landreth, Gary E.; Oblak, Adrian L.; Nho, Kwangsik

doi:10.1016/j.nbd.2021.105303

Cited by 76 publications

(92 citation statements)

References 27 publications

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“…In the ROSMAP dataset, the RNA-seq data were generated from dorsolateral prefrontal cortices. The procedures for sample collection, post-mortem sample descriptions, tissue and RNA preparation methods, library preparation and sequencing methods, and sample quality controls were previously described in detail [ 18 – 22 ].…”

Section: Methodsmentioning

confidence: 99%

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

et al. 2022

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Background Alzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood. Methods Using bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer’s Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology. Results We observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide. Conclusions Our results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.

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Section: Methodsmentioning

confidence: 99%

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

et al. 2022

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“…INPP5D is also a microglia-related gene, involved in LOAD. Studies have reported that INPP5D expression is upregulated with the progression of AD and is detected mainly in the plaque-associated microglia, implicating a deleterious role of increased INPP5D expression in AD (Tsai et al, 2021 ). Consequently, targeting these AD-related risk genes may offer new avenues for AD treatment.…”

Section: Microglia and Admentioning

confidence: 99%

Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

Zhang

Wang

et al. 2021

Front. Cell. Neurosci.

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Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

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“… 51 Recently, Tsai et al, 2021, demonstrated that INPP5D was positively associated with amyloid plaque density in the human brain. 52 Thus, these pieces of evidence concluded that the abovementioned HUB proteins are associated with neurological diseases in some manner through the regulation of different biological phenomena, yet their relationship in the AD and PD crosstalk is still missing. Further, HUB proteins, namely, NUMA1 and NUP93, lack the potential involvement in the pathogenesis of either AD and PD.…”

Section: Results and Discussionmentioning

confidence: 99%

CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

Gupta

Kumar

2021

ACS Omega

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Integration of omics data and deciphering the mechanism of a biological regulatory network could be a promising approach to reveal the molecular mechanism involved in the progression of complex diseases, including Alzheimer’s and Parkinson’s. Despite having an overlapping mechanism in the etiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the exact mechanism and signaling molecules behind them are still unknown. Further, the acetylation mechanism and histone deacetylase (HDAC) enzymes provide a positive direction toward studying the shared phenomenon between AD and PD pathogenesis. For instance, increased expression of HDACs causes a decrease in protein acetylation status, resulting in decreased cognitive and memory function. Herein, we employed an integrative approach to analyze the transcriptomics data that established a potential relationship between AD and PD. Data preprocessing and analysis of four publicly available microarray datasets revealed 10 HUB proteins, namely, CDC42, CD44, FGFR1, MYO5A, NUMA1, TUBB4B, ARHGEF9, USP5, INPP5D, and NUP93, that may be involved in the shared mechanism of AD and PD pathogenesis. Further, we identified the relationship between the HUB proteins and transcription factors that could be involved in the overlapping mechanism of AD and PD. CREB1 and HINFP were the crucial regulatory transcription factors that were involved in the AD and PD crosstalk. Further, lysine acetylation sites and HDAC enzyme prediction revealed the involvement of 15 and 27 potential lysine residues of CREB1 and HINFP, respectively. Our results highlighted the importance of HDAC1(K292) and HDAC6(K330) association with CREB1 and HINFP, respectively, in the AD and PD crosstalk. However, different datasets with a large number of samples and wet lab experimentation are required to validate and pinpoint the exact role of CREB1 and HINFP in the AD and PD crosstalk. It is also possible that the different datasets may or may not affect the results due to analysis parameters. In conclusion, our study potentially highlighted the crucial proteins, transcription factors, biological pathways, lysine residues, and HDAC enzymes shared between AD and PD at the molecular level. The findings can be used to study molecular studies to identify the possible relationship in the AD–PD crosstalk.

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INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia

Cited by 76 publications

References 27 publications

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

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INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia

Cited by 76 publications

References 27 publications

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

CREB1K292 and HINFPK330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

Contact Info

Product

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CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease