title: A novel hypothesis for Alzheimer disease based on neuronal tetraploidy induced by p75 (NTR).
abstract: 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 Aβ 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 p75NTR by an endogenous source of NGF. In contrast, BDNF inhibits G2/M transition in tetraploid RGCs, preventing their death by apoptosis. In AD both proNGF and p75NTR are overexpressed, and AD-associated oxidative conditions have been shown to enhance proNGF function. This suggests that p75NTR could be a trigger for neuronal tetraploidization in AD, being the p75NTR-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 G2/M transition and apoptosis in tetraploid neurons.
authors.affiliation: Instituto Cajal, CSIC, Madrid, Spain. frade@cajal.csic.es
authors.forename: José M
authors.initials: JM
authors.lastname: Frade
authors.forename: Noelia
authors.initials: N
authors.lastname: López-Sánchez
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D057891:Tetraploidy
chemical_list: D020800:Receptor, Nerve Growth Factor