Browsing by Author "Bergmann, Kristy"

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    Circular RNA detection identifies circPSEN1 alterations in brain specific to autosomal dominant Alzheimer's disease
    (BMC, 2022-03-04) Chen, Hsiang‑Han; Eteleeb, Abdallah; Wang, Ciyang; Fernandez, Maria Victoria; Budde, John P.; Bergmann, Kristy; Norton, Joanne; Wang, Fengxian; Ebl, Curtis; Morris, John C.; Perrin, Richard J.; Bateman, Randall J.; McDade, Eric; Xiong, Chengjie; Goate, Alison; Farlow, Martin; Chhatwal, Jasmeer; Schofield, Peter R.; Chui, Helena; Harari, Oscar; Cruchaga, Carlos; Ibanez, Laura; Dominantly Inherited Alzheimer Network; Neurology, School of Medicine
    Background: Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (< 65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD. Methods: We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software. Results: Our results show significant differences in gene counts of circPSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD = 21, AD = 253, Controls = 23-ADADvsCO: log2FC = 0.794, p = 1.63 × 10-04, ADADvsAD: log2FC = 0.602, p = 8.22 × 10-04). The high gene counts are contributed by two circPSEN1 species (hsa_circ_0008521 and hsa_circ_0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circPSEN1 is involved in several pathways such as axon guidance (p = 3.39 × 10-07), hippo signaling pathway (p = 7.38 × 10-07), lysine degradation (p = 2.48 × 10-05) or Wnt signaling pathway (p = 5.58 × 10-04) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70. Conclusions: Our findings show the differential expression of circPSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta.
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    Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains
    (Wiley, 2023) Novotny, Brenna C.; Fernandez, Maria Victoria; Wang, Ciyang; Budde, John P.; Bergmann, Kristy; Eteleeb, Abdallah M.; Bradley, Joseph; Webster, Carol; Ebl, Curtis; Norton, Joanne; Gentsch, Jen; Dube, Umber; Wang, Fengxian; Morris, John C.; Bateman, Randall J.; Perrin, Richard J.; McDade, Eric; Xiong, Chengjie; Chhatwal, Jasmeer; Dominantly Inherited Alzheimer Network (DIAN) Study Group; Alzheimer's Disease Neuroimaging Initiative; Alzheimer's Disease Metabolomics Consortium (ADMC); Goate, Alison; Farlow, Martin; Schofield, Peter; Chui, Helena; Karch, Celeste M.; Cruchaga, Carlos; Benitez, Bruno A.; Harari, Oscar; Neurology, School of Medicine
    Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. Highlights: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.
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    Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
    (Springer Nature, 2023-04-21) Brase, Logan; You, Shih-Feng; D'Oliveira Albanus, Ricardo; Del-Aguila, Jorge L.; Dai, Yaoyi; Novotny, Brenna C.; Soriano-Tarraga, Carolina; Dykstra, Taitea; Fernandez, Maria Victoria; Budde, John P.; Bergmann, Kristy; Morris, John C.; Bateman, Randall J.; Perrin, Richard J.; McDade, Eric; Xiong, Chengjie; Goate, Alison M.; Farlow, Martin; Dominantly Inherited Alzheimer Network (DIAN); Sutherland, Greg T.; Kipnis, Jonathan; Karch, Celeste M.; Benitez, Bruno A.; Harari, Oscar; Neurology, School of Medicine
    Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOEε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser (http://web.hararilab.org/SNARE/).