Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors

Acker, Zoë P. Van; Bretou, Marine; Annaert, Wim

doi:10.1186/s13024-019-0323-7

Cited by 177 publications

(156 citation statements)

References 169 publications

(247 reference statements)

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“…All of these genes are highly or selectively expressed in microglia in the brain 18 . Taken together, our findings implicate dysfunction of the endolysosomal system in myeloid cells (as opposed to neurons 68,69 ) in the etiology of AD. Previous human genetic findings reinforce our conclusion.…”

Section: Discussionmentioning

confidence: 52%

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Novikova

Kapoor

Tcw

et al. 2019

Preprint

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Genome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1 , APBB3 , BIN1 , CD2AP , MS4A4A , MS4A6A , PILRA , RABEP1 , SPI1 , SPPL2A , TP53INP1 , ZKSCAN1 , and ZYX ) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD. causal gene expression in eight loci, and experimentally validated one of these candidate causal variants in the MS4A locus in human induced pluripotent stem cell (hiPSC)-derived microglia. Results AD risk alleles are specifically enriched in active enhancers of monocytes, macrophages and microgliaOur earlier analyses showed a significant enrichment of AD risk alleles in various myeloid-specific epigenomic annotations, but not in brain or other tissues 15 . To further dissect this enrichment, we used ChIP-Seq profiles of histone modifications that define the chromatin signatures of regulatory elements (H3K27ac for active enhancers and promoters, H3K4me1 for enhancers, and H3K4me2 for active enhancers and promoters) from monocytes, macrophages and microglia to annotate the genome with myeloid active enhancers (AE), active promoters (AP), primed enhancers (PE) and primed promoters (PP) (see Methods) [18][19][20] . To identify which of these myeloid regulatory elements are enriched for AD risk alleles, we performed stratified LD score regression (LDSC) 21 of AD single nucleotide polymorphism (SNP) heritability partitioned by the aforementioned epigenomic annotations using the International Genomics of Alzheimer's Project (IGAP) AD GWAS dataset 22 . This analysis revealed selective enrichment of AD risk alleles in active enhancers of monocytes, macrophages and microglia (Figure 1a). In contrast, schizophrenia SNP heritability (using the Psychiatric Genomics Consortium SCZ GWAS dataset as control 23 ) was not enriched in any of these myeloid regulatory elements (Figure 1a). To identify TFs that likely regulate the activity of myeloid enhancers, we performed de novo motif an...

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Section: Discussionmentioning

confidence: 52%

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Novikova

Kapoor

Tcw

et al. 2019

Preprint

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“…The identification of SAD associated genes has already provided novel insight into pathways involved in AD pathology. AD associated genes can be loosely grouped into those involved in Aβ accumulation, NFT formation and spread, cholesterol homeostasis, innate immunity and inflammation, endocytosis, the cytoskeleton, and epigenetics (Karch and Goate, 2015;Van Acker et al, 2019). Interestingly, many AD associated genes are involved in neuroinflammation and immune activation (Figure 1).…”

mentioning

confidence: 99%

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

Frost

Jonas

2019

Front. Aging Neurosci.

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Alzheimer's disease (AD) is marked by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), neuronal death and synaptic loss, and inflammation in the brain. AD research has, in large part, been dedicated to the understanding of Aβ and NFT deposition as well as to the pharmacological reduction of these hallmarks. However, recent GWAS data indicates neuroinflammation plays a critical role in AD development, thereby redirecting research efforts toward unveiling the complexities of AD-associated neuroinflammation. It is clear that the innate immune system is intimately associated with AD progression, however, the specific roles of glia and neuroinflammation in AD pathology remain to be described. Moreover, inflammatory processes have largely been painted as detrimental to AD pathology, when in fact, many immune mechanisms such as phagocytosis aid in the reduction of AD pathologies. In this review, we aim to outline the delicate balance between the beneficial and detrimental aspects of immune activation in AD as a more thorough understanding of these processes is critical to development of effective therapeutics for AD.

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“…The clearance of extracellular Targeting species in case of AD could be objectified with dietary omega-3 fatty acids. Alzheimer's disease is also being characterized by the endo-lysosomal abnormalities and accumulation of Rab5 positive enlarged endosomes followed by detectable Aβ-plaques [16,48]. The accumulation also impairs the fusion of autophagosomes with lateendosomes and lysosomal degradation.…”

Section: Discussionmentioning

confidence: 99%

α-Linolenic acid modulates phagocytosis of extracellular Tau and induces microglial migration

Desale

Chinnathambi

2020

Preprint

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BackgroundSeeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimer's disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory property to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The dietary omega-3 fatty acids are found to change the lipid composition of the cell membrane that predominated many signaling cascade and by modulating specific receptor response. Thus the omega-3 fatty acids influence microglial response in Tauopathy. MethodsN9 microglia cells were exposed to extracellular full-length Tau monomer and aggregates along with ALA (α-Linolenic acid) to study the internalization of exposed Tau. The degradation of internalized Tau studied with the endosomal markers Rab5 and Rab7. The final degradation step in phagocytosis has been studied with LAMP-2A as lysosomal markers. The changes in the rate of migration of microglia were Author's information Affiliations

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Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors

Cited by 177 publications

References 169 publications

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

α-Linolenic acid modulates phagocytosis of extracellular Tau and induces microglial migration

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