Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain.
OBJECTIVE
Increasing evidence suggests a role for oxidative damage to DNA in brain ageing and in neurodegenerative disorders, including Alzheimer's disease. Most studies have focussed on the reduced capacity for DNA repair by neurones, and have not taken into account the effect of oxidative stress on astrocytes, and their contribution to pathology.


METHODS
We examined levels of oxidative stress, DNA damage and DNA repair mechanisms in astrocytes in a population-based sample derived from the Medical Research Council Cognitive Function and Ageing Neuropathology Study.


RESULTS
We demonstrate wide variation in parameters for oxidative stress and DNA damage in astrocytes in the ageing population. We show that there is a significant reduction (P = 0.002) in the lipid peroxidation marker malondialdehyde with increasing Braak stage in Alzheimer's disease. Furthermore, we demonstrate that expression of the DNA damage-associated molecules H2AX and DNA-dependent protein kinase do not increase with increasing Braak stage, rather there is evidence of a nonsignificant reduction in DNA-dependent protein kinase expression by neurones and astrocytes, and in H2AX by neurones with increasing levels of Alzheimer's type pathology.


CONCLUSIONS
These findings suggest that the changes in oxidative stress and the astrocyte DNA damage response are not accounted for as an accumulating effect due to established Alzheimer-type pathology. We hypothesize that astrocyte damage, leading to impaired function, may contribute to the development of ageing brain pathology in some individuals.
Academic Unit of Pathology, University of Sheffield Medical School, Sheffield, UK.
J E
JE
Simpson
P G
PG
Ince
L J
LJ
Haynes
R
R
Theaker
C
C
Gelsthorpe
L
L
Baxter
G
G
Forster
G L
GL
Lace
P J
PJ
Shaw
F E
FE
Matthews
G M
GM
Savva
C
C
Brayne
S B
SB
Wharton
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D004249:DNA Damage / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000096:biosynthesis; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D006657:Histones / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*
C468783:H2AX protein, human; D006657:Histones; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051747:DNA-Activated Protein Kinase; D003849:Deoxyguanosine