Brain Transcriptomic Analysis of Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch Type

Frontiers in Aging Neuroscience

Jeroen F. J. Laros¹  Emile J. de Meijer²  Kristina M. Hettne²  Willeke M. C. van Roon-Mom²  Henk P. J. Buermans²  Peter A. C. ‘t Hoen²  Silvère M. van der Maarel²  Hailiang Mei³  Szymon M. Kiełbasa³  Sjoerd G. van Duinen⁴  Mark A. van Buchem⁵  Linda M. van der Graaf⁵  Louise van der Weerd⁵  Laure Grand Moursel⁵ 

[1] Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands;Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands;Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, Netherlands;Department of Pathology, Leiden University Medical Center, Leiden, Netherlands;Department of Radiology, Leiden University Medical Center, Leiden, Netherlands;

关键词: RNA sequencing and transcriptome analysis;    hereditary cerebral hemorrhage with amyloidosis-Dutch type;    familial cerebral amyloid angiopathy;    E22Q amyloid β;    E693Q mutation;    extracellular matrix remodeling;   

DOI  :  10.3389/fnagi.2018.00102

来源: DOAJ

【 摘 要 】

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the amyloid precursor protein (APP). Post-mortem frontal and occipital cortical brain tissue from nine patients and nine age-related controls was used for RNA sequencing to identify biological pathways affected in HCHWA-D. Although previous studies indicated that pathology is more severe in the occipital lobe in HCHWA-D compared to the frontal lobe, the current study showed similar changes in gene expression in frontal and occipital cortex and the two brain regions were pooled for further analysis. Significantly altered pathways were analyzed using gene set enrichment analysis (GSEA) on 2036 significantly differentially expressed genes. Main pathways over-represented by down-regulated genes were related to cellular aerobic respiration (including ATP synthesis and carbon metabolism) indicating a mitochondrial dysfunction. Principal up-regulated pathways were extracellular matrix (ECM)–receptor interaction and ECM proteoglycans in relation with an increase in the transforming growth factor beta (TGFβ) signaling pathway. Comparison with the publicly available dataset from pre-symptomatic APP-E693Q transgenic mice identified overlap for the ECM–receptor interaction pathway, indicating that ECM modification is an early disease specific pathomechanism.

【 授权许可】

Unknown