A novel hypothesis for Alzheimer's disease based on neuronal tetraploidy induced by p75NTR

Cumulative evidence indicates that neuronal cell cycle re-entry represents an early and critical event in AD, recapitulating known hallmarks of the disease including tau hyperphosphorylation and production of A beta peptide-containing plaques. Neurons that duplicate their DNA are rarely observed to undergo mitosis, and they remain for long time as tetraploid cells, in accordance with the chronic course of the disease. We have recently shown that cell cycle re-entry and somatic tetraploidization occurs during normal development in a subpopulation of RGCs, giving rise to enlarged neurons with extensive dendritic trees. Tetraploization in these neurons occurs in response to the activation of the neurotrophin receptor p75(NTR) by an endogenous source of NGF. In contrast, BDNF inhibits G(2)/M transition in tetraploid RGCs, preventing their death by apoptosis. In AD both proNGF and p75(NTR) are overexpressed, and AD-associated oxidative conditions have been shown to enhance proNGF function. This suggests that p75(NTR) could be a trigger for neuronal tetraploidization in AD, being the p75(NTR)-mediated pathway a putative target for therapeutical intervention. Functional changes in affected neurons, derived from tetraploidy-associated hypertrophy, could compromise neuronal viability. The known decline of BDNF/TrkB expression in AD could facilitate G(2)/M transition and apoptosis in tetraploid neurons.