Dysregulation of neuronal differentiation and cell cycle control in Alzheimer's disease

Degeneration in Alzheimer's disease primarily occurs in those neurons that in the adult brain retain, a high degree of structural plasticity and, is associated with the activation of mitogenic signaling and cell cycle activation. Brain areas affected by neurofibrillary degeneration in Alzheimer's disease are structures involved in the regulation of "higher brain functions" that become increasingly predominant as the evolutionary process of encephalization progresses. The functions these areas subserve require a life-long adaptive reorganization of neuronal connectivity. With the increasing need during evolution to organize brain structures of increasing complexity, these processes of dynamic stabilization and de-stabilization become more and more important but might also provide the basis for an increasing rate of failure. The hypothesis is put forward that it is the labile state of differentiation of a subset of neurons in the adult brain that allows for ongoing morphoregulatory processes after development is completed but at the same time renders these neurons particularly vulnerable. Interferring with neuronal differentiation control might, thus, be a potential strategy to prevent neurodegeneration in Alzheimer's disease and related disorders.