The role of aging and brain-derived neurotrophic factor signaling in expression of base excision repair genes in the human brain

Sofie Lautrup, Camilla Myrup Holst, Anne Yde, Stine Asmussen, Vibeke Thinggaard, Knud Larsen, Lisbeth Schmidt Laursen, Mette Richner, Christian B Vaegter, G Aleph Prieto, Nicole Berchtold, Carl W Cotman, Tinna Stevnsner

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Abstract

DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain. Despite the crucial role of the BER pathway, insights into how this pathway is affected by aging in the human brain and the underlying regulatory mechanisms are very limited. By microarray analysis of four cortical brain regions from humans aged 20-99 years (n = 57), we show that the expression of core BER genes is largely downregulated during aging across brain regions. Moreover, we find that expression of many BER genes correlates positively with the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the human brain. In line with this, we identify binding sites for the BDNF-activated transcription factor, cyclic-AMP response element-binding protein (CREB), in the promoter of most BER genes and confirm the ability of BDNF to regulate several BER genes by BDNF treatment of mouse primary hippocampal neurons. Together, these findings uncover the transcriptional landscape of BER genes during aging of the brain and suggest BDNF as an important regulator of BER in the human brain.

OriginalsprogEngelsk
Artikelnummere13905
TidsskriftAging Cell
Vol/bind22
Nummer9
Antal sider20
ISSN1474-9718
DOI
StatusUdgivet - sep. 2023

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