Regional mosaic genomic heterogeneity in the elderly and in Alzheimer's disease as a correlate of neuronal vulnerability.

摘要: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by fibrillary aggregates of Aβ peptide and tau protein. The distribution these pathological hallmarks throughout the brain not random; it follows predictive pattern that used for staging. However, most etiopathogenetic concepts, irrespective whether they focus on or pathology, leave key question unanswered: what explanation different vulnerabilities regions in AD? regional progression neurofibrillary degeneration AD to some extent inversely recapitulates ontogenetic phylogenetic development. Accordingly, preferentially affects areas have recently been acquired restructured during anthropoid evolution, which means involvement neurodevelopmental mechanism highly likely. Since evolutionary expansion neocortex based substantial extension mitotic activity progenitor cells, we propose conceptual link between neurogenesis primates higher risk accumulating errors give rise genomic aberrations commonly referred as DNA content variation (DCV). If increased rates DCV make neurons more vulnerable AD-related one might expect there be rate are affected very early course AD, compared hardly only advanced stages. Therefore, present study, comparatively analyzed five cortical stage (entorhinal cortex), intermediate (temporal, frontal, parietal association late (primary sensory occipital cortex) both normal elderly subjects patients. On average, observed about 10 % neuronal mosaic two- threefold increase We were able demonstrate, moreover, cerebral cortex well patients randomly distributed but instead show systematic differences correspond vulnerability. These findings provide additional evidence heterogeneity may play role pathology.