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Abstract
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.
Highlights
Cerebral amyloid angiopathy (CAA) refers to the presence of amyloid, commonly amyloid β (Aβ), in intracerebral vessels
Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is characterized by severe amyloid angiopathy of meningo-cortical blood vessels; mutation carriers suffer from intracerebral hemorrhage, starting typically between the ages of 40 and 65
High values (>5) were found for three control samples (S_7, S_17, and S_18) and eight HCHWA-D samples (S_19, S_21, S_22, S_23, S_24, S_28, S_32, and S_36), but we did not find a significant correlation with a longer post-mortem delay (PMD) or a lower RNA integrity number (RIN) value
Summary
Cerebral amyloid angiopathy (CAA) refers to the presence of amyloid, commonly amyloid β (Aβ), in intracerebral vessels. CAA pathology is present in the majority of Alzheimer’s disease (AD) brains and is associated with intracerebral hemorrhages in the elderly. Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is a severe monogenic form of CAA with an autosomal dominant pattern of inheritance. A point mutation at codon 693 of the amyloid precursor protein (APP) located at chromosome 21 results in a Transcriptomic Analysis of HCHWA-D Brain glutamine for glutamic acid substitution Glu693Gln) leading to the formation of the Aβ-E22Q peptide, a toxic variant of the Aβ peptide well studied in vitro (Kamp et al, 2014). HCHWA-D is characterized by severe amyloid angiopathy of meningo-cortical blood vessels; mutation carriers suffer from intracerebral hemorrhage, starting typically between the ages of 40 and 65
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