title: Is the time dimension of the cell cycle re-entry in AD regulated by centromere cohesion dynamics?
abstract: Chromosomal involvement is a legitimate, yet not well understood, feature of Alzheimer disease (AD). Firstly, AD affects more women than men. Secondly, the amyloid-β protein precursor genetic mutations, responsible for a cohort of familial AD cases, reside on chromosome 21, the same chromosome responsible for the developmental disorder Down's syndrome. Thirdly, lymphocytes from AD patients display a novel chromosomal phenotype, namely premature centromere separation (PCS). Other documented morphological phenomena associated with AD include the occurrence of micronuclei, aneuploidy, binucleation, telomere instability, and cell cycle re-entry protein expression. Based on these events, here we present a novel hypothesis that the time dimension of cell cycle re-entry in AD is highly regulated by centromere cohesion dynamics. In view of the fact that neurons can re-enter the cell division cycle, our hypothesis predicts that alterations in the signaling pathway leading to premature cell death in neurons is a consequence of altered regulation of the separation of centromeres as a function of time. It is well known that centromeres in the metaphase-anaphase transition separate in a non-random, sequential order. This sequence has been shown to be deregulated in aging cells, various tumors, syndromes of chromosome instability, following certain chemical inductions, as well as in AD. Over time, premature chromosome separation is both a result of, and a driving force behind, further cohesion impairment, activation of cyclin dependent kinases, and mitotic catastrophe, a vicious circle resulting in cellular degeneration and death.
authors.affiliation: Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106.
authors.forename: Vladan P
authors.initials: VP
authors.lastname: Bajić
authors.forename: Biljana
authors.initials: B
authors.lastname: Spremo-Potparević
authors.forename: Lada
authors.initials: L
authors.lastname: Zivković
authors.forename: Ninoslav
authors.initials: N
authors.lastname: Djelić
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith