scholarly journals Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Julio Barrera ◽  
Lingyun Song ◽  
Julia E. Gamache ◽  
Melanie E. Garrett ◽  
Alexias Safi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Unmet Need ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Neuronal Nuclei ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Type Specific

Abstract Background In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation. Methods We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. Results We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. Conclusions Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Graphical Abstract

scholarly journals Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer′s disease brains

2021 ◽  
Author(s):  
Julio A Barrera ◽  
Lingyun Song ◽  
Alexias Safi ◽  
Young Jun Yun ◽  
Melanie E Garrett ◽  
...  
Keyword(s):  
Late Onset ◽  
Unmet Need ◽  
Chromatin Accessibility ◽  
Rna Seq ◽  
Cell Type ◽  
Neuronal Nuclei ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Type Specific ◽  
Load Risk

In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer′s disease (LOAD) and translate the associations to causation. Toward that goal, we conducted ATAC-seq profiling using neuronal nuclear protein (NeuN) sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. In conclusion, using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology.

scholarly journals Cell‐type‐specific and sex‐dependent changes in the chromatin accessibility landscape in late‐onset Alzheimer’s disease brains

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Ornit Chiba‐Falek ◽  
Julio Barrera ◽  
Lingyun Song ◽  
Alexias Safi ◽  
Young Jun Yu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Cell Type Specific

scholarly journals Cell-Type Specific Changes in DNA Methylation of SNCA Intron 1 in Synucleinopathy Brains

2021 ◽  
Vol 15 ◽  
Author(s):  
Jeffrey Gu ◽  
Julio Barrera ◽  
Young Yun ◽  
Susan K. Murphy ◽  
Thomas G. Beach ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Frontal Cortex ◽  
Cpg Island ◽  
Cell Type ◽  
Neuronal Nuclei ◽  
Intron 1 ◽  
Significant Difference ◽  
Dependent Cell ◽  
A Cell ◽  
Cell Type Specific

Parkinson’s disease (PD) and dementia with Lewy body (DLB) are the most common synucleinopathies. SNCA gene is a major genetic risk factor for these diseases group, and dysregulation of its expression has been implicated in the genetic etiologies of several synucleinopathies. DNA methylation at CpG island (CGI) within SNCA intron 1 has been suggested as a regulatory mechanism of SNCA expression, and changes in methylation levels at this region were associated with PD and DLB. However, the role of DNA methylation in the regulation of SNCA expression in a cell-type specific manner and its contribution to the pathogenesis of PD and DLB remain poorly understood, and the data are conflicting. Here, we employed a bisulfite pyrosequencing technique to profile the DNA methylation across SNCA intron 1 CGI in PD and DLB compared to age- and sex-matched normal control subjects. We analyzed homogenates of bulk post-mortem frozen frontal cortex samples and a subset of neuronal and glia nuclei sorted by the fluorescence-activated nuclei sorting (FANS) method. Bulk brain tissues showed no significant difference in the overall DNA methylation across SNCA intron 1 CGI region between the neuropathological groups. Sorted neuronal nuclei from PD frontal cortex showed significant lower levels of DNA methylation at this region compared to normal controls, but no differences between DLB and control, while sorted glia nuclei exhibited trends of decreased overall DNA methylation in DLB only. In conclusion, our data suggested disease-dependent cell-type specific differential DNA methylation within SNCA intron 1 CGI. These changes may affect SNCA dysregulation that presumably mediates disease-specific risk. Our results can be translated into the development of the SNCA intron 1 CGI region as an attractive therapeutics target for gene therapy in patients who suffer from synucleinopathies due to SNCA dysregulation.

scholarly journals Transferrin Biosynthesized in the Brain Is a Novel Biomarker for Alzheimer’s Disease

Metabolites ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 616
Author(s):  
Kyoka Hoshi ◽  
Hiromi Ito ◽  
Eriko Abe ◽  
Takashi J. Fuwa ◽  
Mayumi Kanno ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Neurological Diseases ◽  
Ultra Performance Liquid Chromatography ◽  
Cell Type ◽  
Post Translational Modification ◽  
A Cell ◽  
Cell Type Specific ◽  
The Brain

Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer’s disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed by ultra-performance liquid chromatography followed by mass spectrometry. We found that a unique mannosylated-glycan is carried by a Tf isoform in CSF (Man-Tf). The cerebral cortex contained Man-Tf as a major isofom, suggesting that CSF Man-Tf is, at least partly, derived from the cortex. Man-Tf levels were analyzed in CSF of patients with neurological diseases. Concentrations of Man-Tf were significantly increased in AD and mild cognitive impairment (MCI) comparing with other neurological diseases, and the levels correlated well with those of phosphorylated-tau (p-tau), a representative AD marker. Consistent with the observation, p-tau and Tf were co-expressed in hippocampal neurons of AD, leading to the notion that a combined p-tau and Man-Tf measure could be a biomarker for AD. Indeed, levels of p-tau x Man-Tf showed high diagnostic accuracy for MCI and AD; 84% sensitivities and 90% specificities for MCI and 94% sensitivities and 89% specificities for AD. Thus Man-Tf could be a new biomarker for AD.

scholarly journals Cell Type-Specific Human APP Transgene Expression by Hippocampal Interneurons in the Tg2576 Mouse Model of Alzheimer’s Disease

2019 ◽  
Vol 13 ◽  
Author(s):  
Corinna Höfling ◽  
Emira Shehabi ◽  
Peer-Hendrik Kuhn ◽  
Stefan F. Lichtenthaler ◽  
Maike Hartlage-Rübsamen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Transgene Expression ◽  
Tg2576 Mouse ◽  
Cell Type ◽  
Model Of Alzheimer’S Disease ◽  
Cell Type Specific

scholarly journals Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease

2020 ◽  
Vol 117 (41) ◽  
pp. 25800-25809 ◽  
Author(s):  
Shun-Fat Lau ◽  
Han Cao ◽  
Amy K. Y. Fu ◽  
Nancy Y. Ip
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endothelial Cells ◽  
Transcriptome Analysis ◽  
Cell Type ◽  
Angiogenic Growth Factors ◽  
Cellular Targets ◽  
Therapeutic Development ◽  
Single Nucleus ◽  
Cell Type Specific

Alzheimer’s disease (AD) is the most common form of dementia but has no effective treatment. A comprehensive investigation of cell type-specific responses and cellular heterogeneity in AD is required to provide precise molecular and cellular targets for therapeutic development. Accordingly, we perform single-nucleus transcriptome analysis of 169,496 nuclei from the prefrontal cortical samples of AD patients and normal control (NC) subjects. Differential analysis shows that the cell type-specific transcriptomic changes in AD are associated with the disruption of biological processes including angiogenesis, immune activation, synaptic signaling, and myelination. Subcluster analysis reveals that compared to NC brains, AD brains contain fewer neuroprotective astrocytes and oligodendrocytes. Importantly, our findings show that a subpopulation of angiogenic endothelial cells is induced in the brain in patients with AD. These angiogenic endothelial cells exhibit increased expression of angiogenic growth factors and their receptors (i.e.,EGFL7,FLT1, andVWF) and antigen-presentation machinery (i.e.,B2MandHLA-E). This suggests that these endothelial cells contribute to angiogenesis and immune response in AD pathogenesis. Thus, our comprehensive molecular profiling of brain samples from patients with AD reveals previously unknown molecular changes as well as cellular targets that potentially underlie the functional dysregulation of endothelial cells, astrocytes, and oligodendrocytes in AD, providing important insights for therapeutic development.

scholarly journals Proteinase-Activated Receptor-2 Exerts Protective and Pathogenic Cell Type-Specific Effects in Alzheimer’s Disease

2007 ◽  
Vol 179 (8) ◽  
pp. 5493-5503 ◽  
Author(s):  
Amir Afkhami-Goli ◽  
Farshid Noorbakhsh ◽  
Avril J. Keller ◽  
Nathalie Vergnolle ◽  
David Westaway ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

scholarly journals P4-479: METHODS TO ASSESS CELL-TYPE-SPECIFIC, BIOLOGICAL NETWORKS OF ALZHEIMER'S DISEASE

2019 ◽  
Vol 15 ◽  
pp. P1496-P1496
Author(s):  
Kevin Green ◽  
Elizabeth Blue ◽  
Benjamin A. Logsdon ◽  
Brad Rolf ◽  
Shannon Rose ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Networks ◽  
Cell Type ◽  
Cell Type Specific

scholarly journals Cell Type Specific Expression of Toll-Like Receptors in Human Brains and Implications in Alzheimer’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Henriette R. Frederiksen ◽  
Henriette Haukedal ◽  
Kristine Freude
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cellular Response ◽  
The Body ◽  
Cellular Damage ◽  
Whole Body ◽  
Toll Like Receptors ◽  
Cell Type ◽  
Cell Type Specific ◽  
The Brain

Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer’s disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer’s disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer’s disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer’s disease.

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