The X-chromosome instability phenotype in Alzheimer’s disease: A clinical sign of accelerating aging?

Abstract

Premature centromere division, or premature centromere separation (PCS), occurs when chromatid separation is dysfunctional, occurring earlier than usual during the interphase stage of mitosis. This phenomenon, seen in Robert's syndrome and various cancers, has also been documented in peripheral as well as neuronal cells of Alzheimer's disease (AD). In the latter instances, fluorescent in situ hybridization (FISH), applied to the centromere region of the X-chromosome in interphase nuclei of lymphocytes from peripheral blood in AD patients, demonstrated premature chromosomal separation before mitotic metaphase directly after completion of DNA replication in G 2 phase of the cell cycle. Furthermore, and perhaps unexpectedly given the presumptive post-mitotic status of terminally differentiated neurons, neurons in AD patients also showed significantly increased levels of PCS of the X-chromosome. Taken together with other phenomena such as cell cycle reactivation and ectopic re-expression of cyclins and cycline depedent proteins, we propose that AD is an oncogenic phenotype leading to accelarated aging of the affected brain.

DNA Damage in Alzheimer Disease Lymphocytes and Its Relation to Premature Centromere Division

“…To date no mitosis has been found suggesting that affected neurons do not enter into the M phase of the cell cycle. Alterations such as PCD are considered to be probable proof of cell cycle re-entry [5,22,23] which may lead to premature cell death [39,45] and therefore to neurodegeneration.…”

“…PCD represents a loss of control over sequential separation and segregation of chromosome centromeres, characterized by distinctive separation of chromosomes earlier than usual [20,21]. This phenomenon shows that deregulation of the time of centromere separation can be considered as a manifestation of CIN leading to aneuploidy [19,22,23,24]. Moreover, our previous data suggests that PCD is a distinctive feature of AD, rather than an epiphenomenon of chronological ageing [7].…”

Cell Cycle Deregulation in the Neurons of Alzheimer’s Disease

“…Interestingly, these markers are found in the cytoplasm of AD neurons rather than in the nucleus, their typical site of action (Vincent et al 1997). Also, M-phase markers are found in AD neurons: increased MPM2 phosphoepitopes, Cdc25 A and B phosphatases, and binucleation, which may result of abortive mitotic karyokinesis (Vincent et al 1998, 2001; Ding et al 2000; Spremo-Potparevic et al 2008; Zhu et al 2008; Bajic et al 2009). The ubiquitination system is also altered in AD (including ubiquitin-1 mutations; Tan et al 2007; Tank and True 2009), which may influence both neuronal cell cycle regulation (Kubiak and Smith 2010) and, protein aggregation and accumulation (Haapasalo et al 2010).…”

Premature centromere division (PCD) identified in a hucul mare with reproductive difficulties

“…Premature centromere division is acknowledged as a pro‐oncogenic phenotype by Zivković and colleagues (Bajić et al, ; Zivković, Spremo‐Potparević, & Djelić, ; Zivković et al, ) where they analysed the phenomenon of chromosome instability in age‐related disease, Alzheimer patients (AD). They described increased PCD related to exclusively X chromosome in female patients, whereas PCD of acrocentric chromosomes were still present in AD patients regardless of age or sex.…”