Mohan, Adith;
Thalamuthu, Anbupalam;
Mather, Karen A.;
Sachdev, Perminder S.
Towards a better understanding of human brain ageing: An RNA sequencing study of neuroinflammatory, neurotransmission‐related and synaptic genes in two key brain regions over the lifespan
: Genetics/molecular genetics
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Medientyp:
E-Artikel
Titel:
Towards a better understanding of human brain ageing: An RNA sequencing study of neuroinflammatory, neurotransmission‐related and synaptic genes in two key brain regions over the lifespan
:
Genetics/molecular genetics
Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Neuroinflammation, synaptic function, and neurotransmission are implicated in gene expression studies of human brain aging. We examined 869 genes specific to these 3 pathways using RNA sequencing in 2 age‐critical brain regions of the human brain, the dorsolateral prefrontal cortex (DLPFC) and posterior cingulate cortex (PCC) in a post‐mortem cohort of 67 non‐diseased control individuals aged 36‐103 years.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Post mortem brain tissue was obtained from the Human Brain Collection Core (HBCC), , NIMH (n = 41, mean age 56y, 25 male) and the Sydney Brain Bank (n = 26, mean age 91y, 12 male) with 2 samples (1 each from the DLPFC and the PCC) per control participant. Controls were free of neurological disease at the time of death. Additionally, tissue samples did not meet pathological criteria for neurological or neurodegenerative disease and were stroke free in the regions of interest. RNA extraction and library preparation used standard protocols with rRNA depletion (TruSeq Stranded Ribozero prep). 100 base pair paired end reads were obtained on a NovaSeq S4 (Illumina) with a minimum of 50 million paired reads per sample. Standard bioinformatics pipeline was used to process raw read data into normalised gene expression values. We examined relationship of age with gene expression adjusted for gender, post‐mortem interval and library size using regression analyses corrected for multiple testing. Candidate gene lists were derived from public gene‐ontology databases namely KEGG and PANTHER as well as a previously published set of microglia‐derived genes (Butovsky, et al., 2014).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>320 and 204 genes from our candidate pathways showed significant differential expression with age in the DLPFC and PCC respectively. The majority of these were upregulated with age in both cortical regions. More than 80% of upregulated genes across both regions were neuroinflammation related, and most upregulated neurotransmission genes encoded elements of the glutamatergic transmission. Genes related to synaptic elements were almost exclusively downregulated with age. 151 genes were significant in both regions and followed the same age‐related pattern as above.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our findings support the prominence of neuroinflammation and excitotoxicity as prominent drivers of molecular brain aging. Further network analyses are planned including eQTL analyses.</jats:p></jats:sec>