The interaction between aging and DNA damage influences the accumulation of APP in Alzheimer's disease

DNA damage is a major driver of the aging process. The progression of Alzheimers disease (AD) worsens the situation as evidenced by the finding that the neurons of the AD brain have elevated levels of DNA damage. AD is also associated with the amyloid precursor protein (APP) known for its proteolytic peptide fragment, A{beta}. In the current work we find that these three elements - age, DNA damage, and APP - are associated with each other and present evidence in the mouse brain supporting the hypothesis that DNA damage is the likely cause of the increased APP levels. Using the TUNEL reaction to track DNA damage, we show that the TUNEL staining increases significantly with age (6 months to 24 months). Next, we used immunostaining of intracellular APP to show that it too increases over this same time period. To separate correlation from causality we repeated these analyses using tissue from mice genetically deficient in the ATM (ataxia-telangiectasia mutated) kinase, an enzyme associated with part of the DNA damage repair mechanism. TUNEL signal in neurons of 6-month Atm-/- animals was equivalent to that seen in 24-month wild type. Significantly, the APP signal in the Atm-/- cells increased in consort and the relationship between DNA damage and APP was found in both neuronal and non-neuronal cells. These results suggest that the loss of genomic integrity associated with aging is a cellular stressor that increases the levels of APP and thus increases vulnerability to the pathogenesis of AD.