Alzheimer's disease as a loss of differentiation control in a subset of neurons that retain immature features in the adult brain

Degeneration in AD primarily occurs in a subset of neurons that in the adult brain retain a high degree of structural plasticity and in these neurons is associated with the activation of mitogenic pathways and a cell cycle re-entry. Brain areas affected by AD pathology are those structures involved in the regulation of higher brain functions that become increasingly predominant as the evolutionary process of encephalization progresses, such as hippocampus. neocortical association areas and the cholinergic basal forebrain neurons. The functions these areas subserve such as learning, memory, perception, self-awareness. and consciousness require a life-long re-fitting of synaptic contacts that allows for the acquisition of new epigenetic information. This adaptive reorganization of neuronal connectivity in the mature brain is based upon the strengthening of existing synapses, the formation of new synapses and the destabilization of previously established synaptic contacts. 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. A hypothesis is proposed that it is the 'labile state of differentiation' (G(0)-arrest) 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. The delicate balance between G(0)-arrest and G(1)-entry might be prone to a variety of potential disturbances during the lifetime of an individual. Morphodysregulation in AD, accompanied by an activation of intracellular mitogenic signaling might, thus, be a slowly progressing dysfunction that eventually overrides the differentiation control and results in dedifferentiation, a condition in conflict with the otherwise 'mature' background of the nervous system. Cell-cycle and differentiation control might thus provide the link between structural brain self-organization and neurodegeneration that both are unique to human. (C) 2000 Elsevier Science Inc. All rights reserved.