DNA repair deficiency for alkylation damage in cells from Alzheimer's disease patients.
We have shown that fibroblasts, lymphocytes and lymphoblasts from patients with Alzheimer's disease (AD) are deficient in the repair of DNA damage induced by the alkylating agents methylmethane sulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Unscheduled DNA synthesis and alkaline elution studies of DNA repair using human skin fibroblasts obtained from patients coming to autopsy have shown that the cells from autopsy confirmed cases of AD have lower levels of DNA repair synthesis after exposure to varying concentrations of either MMS or MNNG. Lymphoblasts derived from individuals with dominantly inherited AD have also been used to study DNA repair. Alkaline elution analysis of DNA repair after exposure to 200 uM MMS or 6 uM MNNG indicates that there is significantly less repair in the lymphoblasts from AD patients. When healthy control cell lines repaired and cell lines from AD patients were exposed to MMS or MNNG respectively significantly less repair occurred in the AD cells. After studying five at risk individuals results indicate that cell lines from two of these people have low levels of DNA repair and three lines have normal repair. These findings support the hypothesis of a DNA repair deficiency in familial AD. Monocytes from healthy control subjects and putative AD patients were analyzed for mutant frequency and DNA repair capacity. Results of unscheduled DNA synthesis experiments using monocytes from 7 healthy controls and 9 presumed AD patients indicates that there is a decreased ability of AD cells to repair MMS and MNNG induced DNA damage.
Bradley
W G
WG
Department of Neurology, University of Vermont, Burlington.
Polinsky
R J
RJ
Pendlebury
W W
WW
Jones
S K
SK
Nee
L E
LE
Bartlett
J D
JD
Hartshorn
J N
JN
Tandan
R
R
Sweet
L
L
Magin
G K
GK
D000477:Alkylating Agents / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism
D000477:Alkylating Agents; D008769:Methylnitronitrosoguanidine; D008741:Methyl Methanesulfonate