Genetics of the human microglia regulome refines Alzheimer’s disease risk loci

Kosoy, Roman; Fullard, John F.; Zeng, Biao; Bendl, Jaroslav; Dong, Pengfei; Rahman, Shadab A.; Kleopoulos, Steven P.; Shao, Zhiping; Girdhar, Kiran; Humphrey, Jack; Lopes, Kátia de Paiva; Charney, Alexander; Kopell, Brian H.; Raj, Towfique; Bennett, David A.; Kellner, Christopher P.; Haroutunian, Vahram; Hoffman, Gabriel E.; Roussos, Panos

doi:10.1038/s41588-022-01149-1

Cited by 61 publications

(75 citation statements)

References 69 publications

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“…In addition to risk gene identification by GWAS, the integration of a multi-omic dataset allows fine mapping of AD risk loci. For instance, examining the population-level variation of gene expression and incorporating chromatin accessibility could verify previously implicated AD risk genes and identify putative AD genes for loci harboring multiple candidate genes (e.g., MS4A4E in the MS4A gene cluster) [ 188 ]. Such approaches could provide support for the microglial PU.1 transcription factor that has previously been associated with increased AD risk [ 189 , 190 ].…”

Section: Microglial Activation In Admentioning

confidence: 99%

“…Such approaches could provide support for the microglial PU.1 transcription factor that has previously been associated with increased AD risk [ 189 , 190 ]. The PU.1 downstream target genes have a predominantly immune function, in particular, the contributions of myeloid-/leukocyte-related processes were strongly highlighted [ 188 ]. This resource for human microglia-specific regulation of transcription provides further evidence for the critical role of microglia in AD.…”

Section: Microglial Activation In Admentioning

confidence: 99%

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The neuroimmune axis of Alzheimer’s disease

2023

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Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD.

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Section: Microglial Activation In Admentioning

confidence: 99%

Section: Microglial Activation In Admentioning

confidence: 99%

The neuroimmune axis of Alzheimer’s disease

2023

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“…Several independent studies have recently reported a significant association of the LOAD-susceptibility PICALM risk variants (rs10792832 and rs3851179 that are in full LD) on the decreased expression in microglial cells [ 90 , 91 ]. It should be highly informative to create AD models in which microglial PICALM expression is modulated in order to unravel the effect of reduced or increased PICALM expression in microglia.…”

Section: Discussionmentioning

confidence: 99%

“…Analyses on expression quantitative trait loci (eQTL) suggest that there may be a cell-type specific effect of the PICALM variant, notably in microglia. Several recent PICALM eQTL analyses have consistently suggested that there is a significant colocalization between AD GWAS signals and PICALM eQTL in microglia [ 90 , 91 , 92 , 93 ]. PICALM rs10792832 (in almost full LD with rs3851179) is located in an open chromatin region (OCR), and the non-protective variant was associated with both lower OCR signal and gene expression by regulating chromatin accessibility [ 91 ].…”

Section: Picalm and Alzheimer’s Disease Pathologymentioning

confidence: 99%

PICALM and Alzheimer’s Disease: An Update and Perspectives

Ando

Nagaraj

Küçükali

et al. 2022

Cells

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Genome-wide association studies (GWAS) have identified the PICALM (Phosphatidylinositol binding clathrin-assembly protein) gene as the most significant genetic susceptibility locus after APOE and BIN1. PICALM is a clathrin-adaptor protein that plays a critical role in clathrin-mediated endocytosis and autophagy. Since the effects of genetic variants of PICALM as AD-susceptibility loci have been confirmed by independent genetic studies in several distinct cohorts, there has been a number of in vitro and in vivo studies attempting to elucidate the underlying mechanism by which PICALM modulates AD risk. While differential modulation of APP processing and Aβ transcytosis by PICALM has been reported, significant effects of PICALM modulation of tau pathology progression have also been evidenced in Alzheimer’s disease models. In this review, we summarize the current knowledge about PICALM, its physiological functions, genetic variants, post-translational modifications and relevance to AD pathogenesis.

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“…This, as well as previous studies, brought forward the idea that the balance of ubiquitinylation leading to protein degradation may be disrupted in AD and PD leading to protein accumulation. At the same time, Genome Wide Association Studies (GWAS) implicate numerous innate immune genes as risk factors for late onset AD in a glial transcriptional network (Kosoy et al, 2022;Matarin et al, 2015;Salih et al, 2019;Sims et al, 2017). This suggests that genetic differences (as defined by GWAS) in the response to the normal age-dependent increase in inflammatory activity may lead to late onset AD (Fulop et al, 2021 for review).…”

Section: Discussionmentioning

confidence: 99%

Sex-specific deubiquitylation drives immune-related neurodegeneration inDrosophila

Xia

Pinto-Fernández

Damianou

et al. 2022

Preprint

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Risk of neurodegenerative disease such as late onset Alzheimers is linked to aberrant ubiquitinylation and accumulation of non-degraded proteins in brain cells. A glial network of innate immune genes modulates inflammatory responses to such protein deposition. However, vulnerability differs between the sexes. Here, we show that the Drosophila homologue of the deubiquitylase Trabid can align the sex-specific aspects of neurodegenerative phenotypes with changes in ubiquitylation and inflammatory activity. An enzymatically null Trabid in flies, caused sex-specific changes in locomotion, sleep patterns, brain histology and ultimately, lifespan. These changes were underscored by altered ubiquitin and proteome enrichment profiles and the same enzymatic activity as its human counterpart. When the sex-determination gene transformer was silenced in astrocytes or immunocompetent tissues, sex differences were significantly reduced. Our results indicate that Trabid underscores sex-specificity in disease neurology, by controlling the balance between ubiquitylation and inflammation.

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Genetics of the human microglia regulome refines Alzheimer’s disease risk loci

Cited by 61 publications

References 69 publications

The neuroimmune axis of Alzheimer’s disease

The neuroimmune axis of Alzheimer’s disease

PICALM and Alzheimer’s Disease: An Update and Perspectives

Sex-specific deubiquitylation drives immune-related neurodegeneration inDrosophila

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