Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk

Efthymiou, Anastasia G.; Goate, Alison M.

doi:10.1186/s13024-017-0184-x

Cited by 456 publications

(396 citation statements)

References 99 publications

Supporting

Mentioning

380

Contrasting

Unclassified

Order By: Relevance

“…We aimed to further understand for each of the top 18 genes what the microglial contribution was to the observed increased expression in the bulk RNA-seq data. A regression model was used to assess how well the bulk RNA-seq expression data for a specific Genes are depicted in their known cellular components, with previously described established GWAS (Efthymiou & Goate, 2017;Verheijen & Sleegers, 2018) in black and the prioritized novel genes (this paper) in red. See discussion section for further functional annotation and references.…”

Section: Single Microglia Sequencing Confirms High Proportions Of Actmentioning

confidence: 99%

“…Genetic background strongly determines the risk of sporadic Alzheimer's disease (AD) (Gatz et al, 2006). Unlike the APOE4 polymorphism and 42 other genetic loci, thousands of SNPs associated with risk of AD do not reach genome-wide significance (Efthymiou & Goate, 2017;Marioni et al, 2018;Verheijen & Sleegers, 2018). Polygenic risk scores (PRSs) incorporate the contributions of these variations and relate these contributions to disease risk (Purcell et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

et al. 2020

View full text Add to dashboard Cite

Polygenic risk scores have identified that genetic variants without genome‐wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy‐TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome‐wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.

show abstract

Section: Single Microglia Sequencing Confirms High Proportions Of Actmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

et al. 2020

View full text Add to dashboard Cite

show abstract

“…As a multitude of microglial genes have recently been implicated in modulating AD risk (Efthymiou & Goate, 2017;Guerreiro, Wojtas, et al, 2013;Hansen, Hanson, & Sheng, 2018;Huang et al, 2017;Jansen et al, 2019;Jonsson et al, 2013;Kunkle et al, 2019;Lambert et al, 2013;Sims et al, 2017), studies that carefully analyze these risk genes will be critical for enhancing our understanding of AD pathogenesis. Therefore, it is not surprising that some of the first iMG studies examined functions related to AD neuropathology.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

Hasselmann

Blurton‐Jones

2020

Glia

View full text Add to dashboard Cite

Recent advances in the generation of microglia from human induced pluripotent stem cells (iPSCs) have provided exciting new approaches to examine and decipher the biology of microglia. As these techniques continue to evolve to encompass more complex in situ and in vivo paradigms, so too have they begun to yield novel scientific insight into the genetics and function of human microglia. As such, researchers now have access to a toolset comprised of three unique “flavors” of iPSC‐derived microglia: in vitro microglia (iMGs), organoid microglia (oMGs), and xenotransplanted microglia (xMGs). The goal of this review is to discuss the variety of research applications that each of these techniques enables and to highlight recent discoveries that these methods have begun to uncover. By presenting the research paradigms in which each model has been successful, as well as the key benefits and limitations of each approach, it is our hope that this review will help interested researchers to incorporate these techniques into their studies, collectively advancing our understanding of human microglia biology.

show abstract

“…They are also localized in immune cells, particularly the B cell lymphocyte [59][60][61][62]. AD genes are also predominantly expressed in microglial cells, the resident macrophage/immune cells of the brain [63,64].…”

Section: Introductionmentioning

confidence: 99%

Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Carter

2017

ADR

View full text Add to dashboard Cite

Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans, Cryptococcus neoformans, Bornavirus, Borrelia burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae, Porphyrymonas gingivalis, Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy.

show abstract

Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk

Cited by 456 publications

References 99 publications

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Contact Info

Product

Resources

About