scholarly journals Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2866
Author(s):  
Anna Mallach ◽  
Johan Gobom ◽  
Charles Arber ◽  
Thomas M. Piers ◽  
John Hardy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Risk Variant ◽  
Human Microglia ◽  
Increased Risk ◽  
Neuronal Processes ◽  
The Common ◽  
Communication Pathway ◽  
Stimulation Of

Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer’s disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common TREM2 variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47Hhet TREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant.

scholarly journals Differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons

2021 ◽  
Author(s):  
Anna Mallach ◽  
Johan Gobom ◽  
Charles Arber ◽  
Thomas M Piers ◽  
John Hardy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Risk Variant ◽  
Human Microglia ◽  
Inflammatory Signals ◽  
Increased Risk ◽  
Neuronal Processes ◽  
Communication Pathway ◽  
Stimulation Of

Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of the triggering receptor expressed myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer's disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease associated microglial (DAM) signature proteins, and were less able to promote outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from TREM2 common variant iPS-Mg. Taken together these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47HhetTREM2 variant may underlie the increased risk of Alzheimer's disease associated with this variant.

scholarly journals Alzheimer's Disease Risk Gene, GAB2, is Associated with Regional Brain Volume Differences in 755 Young Healthy Twins

2012 ◽  
Vol 15 (3) ◽  
pp. 286-295 ◽  
Author(s):  
Derrek P. Hibar ◽  
Neda Jahanshad ◽  
Jason L. Stein ◽  
Omid Kohannim ◽  
Arthur W. Toga ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Young Adult ◽  
Disease Risk ◽  
Adult Brain ◽  
Brain Morphology ◽  
Control Analysis ◽  
Risk Gene ◽  
Increased Risk ◽  
The Brain

The development of late-onset Alzheimer's disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer's disease risk gene, growth factor receptor bound protein 2-associated protein (GAB2), has been shown to provide a 1.27–1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young adult twins (469 females) (M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer's disease.

scholarly journals Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults

2011 ◽  
Vol 31 (18) ◽  
pp. 6764-6770 ◽  
Author(s):  
M. N. Braskie ◽  
N. Jahanshad ◽  
J. L. Stein ◽  
M. Barysheva ◽  
K. L. McMahon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Young Adults ◽  
White Matter ◽  
Disease Risk ◽  
Risk Variant ◽  
White Matter Microstructure

CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism

2009 ◽  
Vol 24 (3) ◽  
pp. 183-190 ◽  
Author(s):  
Heike Kölsch ◽  
Dieter Lütjohann ◽  
Frank Jessen ◽  
Julius Popp ◽  
Frank Hentschel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Cholesterol Metabolism ◽  
Disease Risk ◽  
Brain Cholesterol ◽  
Increased Risk ◽  
Csf Levels ◽  
Interaction Term ◽  
Gene Variability

AbstractBackgroundCholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.MethodsWe performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.ResultsTwo of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).ConclusionOur results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

scholarly journals Genetics of the human microglia regulome refines Alzheimer's disease risk loci

2021 ◽  
Author(s):  
Roman Kosoy ◽  
John Fullard ◽  
Biao Zeng ◽  
Jaroslav Bendl ◽  
Pengfei Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Regulatory Networks ◽  
Disease Risk ◽  
Single Gene ◽  
Critical Role ◽  
Chromatin Accessibility ◽  
Human Microglia ◽  
Mapping Analysis ◽  
Regulatory Landscape

Microglia are brain resident myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer's Disease (AD). Yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to disease is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically-driven variation and cell-specific enhancer-promoter interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 novel genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides novel insights into the etiology of neurodegenerative disease.

Alzheimer's disease risk variant in CLU is associated with neural inefficiency in healthy individuals

2014 ◽  
Vol 11 (10) ◽  
pp. 1144-1152 ◽  
Author(s):  
Thomas M. Lancaster ◽  
Lisa M. Brindley ◽  
Katherine E. Tansey ◽  
Rebecca C. Sims ◽  
Kiran Mantripragada ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Healthy Individuals ◽  
Risk Variant

scholarly journals Androgen Deprivation Therapy and Future Alzheimer’s Disease Risk

2016 ◽  
Vol 34 (6) ◽  
pp. 566-571 ◽  
Author(s):  
Kevin T. Nead ◽  
Greg Gaskin ◽  
Cariad Chester ◽  
Samuel Swisher-McClure ◽  
Joel T. Dudley ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Propensity Score ◽  
Medical Record ◽  
Disease Risk ◽  
Medical Record Data ◽  
Electronic Medical Record Data ◽  
Increased Risk ◽  
Record Data

Purpose To test the association of androgen deprivation therapy (ADT) in the treatment of prostate cancer with subsequent Alzheimer’s disease risk. Methods We used a previously validated and implemented text-processing pipeline to analyze electronic medical record data in a retrospective cohort of patients at Stanford University and Mt. Sinai hospitals. Specifically, we extracted International Classification of Diseases-9th revision diagnosis and Current Procedural Terminology codes, medication lists, and positive-present mentions of drug and disease concepts from all clinical notes. We then tested the effect of ADT on risk of Alzheimer’s disease using 1:5 propensity score–matched and traditional multivariable-adjusted Cox proportional hazards models. The duration of ADT use was also tested for association with Alzheimer’s disease risk. Results There were 16,888 individuals with prostate cancer meeting all inclusion and exclusion criteria, with 2,397 (14.2%) receiving ADT during a median follow-up period of 2.7 years (interquartile range, 1.0-5.4 years). Propensity score–matched analysis (hazard ratio, 1.88; 95% CI, 1.10 to 3.20; P = .021) and traditional multivariable-adjusted Cox regression analysis (hazard ratio, 1.66; 95% CI, 1.05 to 2.64; P = .031) both supported a statistically significant association between ADT use and Alzheimer’s disease risk. We also observed a statistically significant increased risk of Alzheimer’s disease with increasing duration of ADT (P = .016). Conclusion Our results support an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer’s disease in a general population cohort. This study demonstrates the utility of novel methods to analyze electronic medical record data to generate practice-based evidence.

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