Alzheimer's disease as a disorder of dynamic brain self-organization

Mental function is based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits), involved in the realization of "higher brain functions" such as learning, memory, perception, self-awareness, and consciousness, are continuously re-adjusted even after development is completed. By this life-long self-optimization process, epigenetic information remodels the cognitive, behavioral and emotional reactivity of an individual to meet the environmental demands. To organize brain structures of increasing complexity during evolution, the process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. The mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodeling according to experience, are accompanied, however, by an increasing inherent potential of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time may provide the basis for selective neuronal vulnerability. The mechanisms of synaptic plasticity, i.e., of modifiable interneuronal connectivity, are largely based on external morphoregulatory cues and internal signaling pathways that nonneuronal cells have phylogenetically acquired to sense their relationship to the local neighborhood and to control proliferation and differentiation in the process of tissue repair and regeneration after development is completed. Differentiated neurons that have withdrawn from the cell cycle use these molecular machinery alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it on the risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration.