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

TY - JOUR

T1 - The role of aging and brain-derived neurotrophic factor signaling in expression of base excision repair genes in the human brain

AU - Lautrup, Sofie

AU - Myrup Holst, Camilla

AU - Yde, Anne

AU - Asmussen, Stine

AU - Thinggaard, Vibeke

AU - Larsen, Knud

AU - Laursen, Lisbeth Schmidt

AU - Richner, Mette

AU - Vaegter, Christian B

AU - Prieto, G Aleph

AU - Berchtold, Nicole

AU - Cotman, Carl W

AU - Stevnsner, Tinna

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

KW - DNA repair

KW - aging

KW - base excision repair

KW - brain

KW - brain-derived neurotrophic factor

KW - cyclic-AMP response element-binding protein

KW - neurons

KW - Aging/genetics

KW - Humans

KW - Signal Transduction/genetics

KW - Brain-Derived Neurotrophic Factor/genetics

KW - DNA Repair/genetics

KW - Animals

KW - Mice

KW - Brain/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85162248395&partnerID=8YFLogxK

U2 - 10.1111/acel.13905

DO - 10.1111/acel.13905

M3 - Journal article

C2 - 37334527

SN - 1474-9718

VL - 22

JO - Aging Cell

JF - Aging Cell

IS - 9

M1 - e13905

ER -