Cell-Type-Specific Differences in Age-Related Changes of DNA Repair in the Mouse Brain - Molecular Basis for a New Approach to Understand the Selective Neuronal Vulnerability in Alzheimer's Disease.

Despite intensive research over the last decades, the molecular basis of the selective neuronal vulnerability in Alzheimer's disease (AD) is still largely unknown. In this context we have recently shown by means of quantitative autoradiography that presumably all types of neurons in the mouse brain suffer an age-related decrease in the rate of mitochondrial DNA synthesis, while in contrast only some distinct types of neurons showed a decrease in the rate of spontaneous overall nuclear DNA repair measured as unscheduled nuclear DNA synthesis. Most strikingly, there was a highly positive correlation to be found between that group of neurons in the mouse brain showing the age-related decrease in the rate of spontaneous overall nuclear DNA repair (pattern X) and the pattern of neurons in the human brain which - according to the literature - are affected by the formation of neurofibrillary tangles in AD (pattern Y). To minimize the risk that this correlation was a result of mere chance based on the selection of the nine types of neurons investigated thus far, in the present study nine further types of neurons in phylogenetically different regions of the mouse brain were investigated by using the same method. An age-related decrease in the rate of spontaneous overall nuclear DNA repair was found only for projection neurons of brain areas with a more plastic, variable and/or malleable structure over phylogenesis but neither for projection neurons of brain areas with a more rigid, invariant and/or conservative structure over phylogenesis nor for interneurons. The obtained results confirmed the highly positive correlation between the aforementioned patterns X and Y. Together with a wealth of data from the literature regarding age-related neuron loss in both the rodent and the human brain, these results may indeed indicate a new approach for understanding the selective neuronal vulnerability in AD.