Guanine-quadruplexes are increased in mild cognitive impairment and correlate with cognitive function and chromosomal DNA damage

Abstract

Guanine-quadruplexes (G4) are highly stable DNA secondary structures known to mediate gene regulation and to trigger genomic instability events during replication. G4 are known to be associated with DNA damage and we propose that G4 are involved in the ageing disorder mild cognitive impairment (MCI). Lymphocytes were obtained from healthy controls and individuals with MCI. The intensity and frequency of G4 foci as well as γH2AX (a marker of DNA damage) intensity were measured by quantitative immunofluorescence and were correlated with cognitive function and cytokinesis-block micronucleus cytome markers of DNA damage. γH2AX intensity as well as G4 frequency and intensity were significantly elevated in MCI lymphocytes compared to controls. The combined biomarker panel was tested in a predictive statistical model, which improved the demarcation of MCI from controls with 80.3% accuracy. The results obtained from this pilot study showed for the first time that G4 levels are increased with cognitive impairment and thus, may be involved in the early development of Alzheimer’s disease possibly via an association with chromosomal DNA damage and DNA double strand breaks.