Late Phase Cell-Cycle Proteins in Postmitotic Neurons: Relation to Alzheimer’s Disease?

Review Article

Austin Alzheimers J Parkinsons Dis. 2014;1(2): 8.

Late Phase Cell-Cycle Proteins in Postmitotic Neurons: Relation to Alzheimer’s Disease?

Bajic VP1*, Stanimirovic J1, Obradovic M1,Zivkovic L2,Milicevic Z1 and Spremo-Potparevic B2

1Vinca Institute of Nuclear Sciences, University of Belgrade, Serbia

2Department of Pharmacy, University of Belgrade, Serbia

*Corresponding author: Bajic VP, Laboratory of Radiobiology and Molecular Genetics, Vinca Institute for Nuclear Sciences, University of Belgrade, P.O Box 522, 11001 Belgrade.

Received: August 27, 2014; Accepted: September 20, 2014; Published: September 25, 2014


Cell cycle re-entry has become a well established model of neuropathogenesis in Alzheimer’s disease (AD). We and others have demonstrated expression of early phase cell cycle-related proteins in the vulnerable neurons in AD. Evidence that this represents a bona fide mitotic event is verified by the observation that DNA replication does in fact occur in these cells. Notably, the relatively early occurrence of cell cycle events in AD suggests that a mitotic cell cycle related mechanism may play a pivotal role in the disease. Still, a number of features of the cell cycle re-entry phenotype have remained elusive to the role of ectopic protein expression in the process of neuronal cell death. Late phase cell cycle proteins regulate separation and segregation of chromosomes. The centromere region is crucial to this process. Until recently there has been no data on the role of proteins controlling the centromere region in postmitotic neurons. This new data suggests that cohesin complexes that mediate sister–chromatid cohesion in dividing cells may also contribute to gene regulation in postmitotic cells. Therefore, centromere-cohesin proteins may play a secondary role in the cell, i.e. one that is independent of their role in cohesion and chromosome segregation. Evidence demonstrating that instability of centromere-cohesion dynamics in the early phases of the cell cycle which coincide with re-entry alteration of cortical neurons enables the possibility to further elucidate initial processes leading to AD.

Keywords: Alzheimer’s Disease; Cell-cycle reentry; Centromere; Cohesin


AD: Alzheimer’s disease; APC: Anaphase Promoting Complex; APLP2: Amyloid Precursor-Like Protein 2; APP: Amyloid Precursor Protein; Aβ: Amyloid-β; Cdc20: Cell-Division Cycle Protein 20; Cdh1: Cdc20-Homologue 1; CDK: Cyclin Dependent Kinase; GSK3β: Glycogen Synthase Kinase 3 β; NFT: Neuro Fibrillary Tangle; NR: N-methyl-D-aspartate Receptor; PCD: Premature Centromere Division; PSD-95: Postsynaptic Density-95; PTTG: Pituitary Tumor Transforming Gene; SAC: Spindle Assembly Checkpoint; Scc: Sister Chromatide Cohesion Protein; SMC: Structural Maintenance of Chromosome; TIM-1: Timeless 1


The canonical markers of AD are extracellular senile plaque composed primarily of fibrilar amyloid-β (Aβ) peptides, and the intracellular neurofibrillary tangle (NFT), a mass of irregularly folded proteins composed mainly of hyperphosphorylated tau protein. The causes and consequences of both Aβ and tau accumulation are a primary focus in the field. In particular, the relationship between tau and Aβ on other mechanisms known to be involved in disease pathogenesis has garnered considerable attention. In this regard changes involving cell cycle dynamics appear to be centrally involved. Indeed, the intracelullar accumulation of highly phosphorylated tau is linked to the cell cycle and cell cycle dependent kinases [1]. Cell senescence, oxidative stress, misregulated apoptosis are important factors in the pathogenesis of AD [1,2] and are influenced by aberrations in the cell cycle dynamics and, in particular, telomere length. Notably, the link between cell cycle related events and apoptosis is becoming increasingly recognized in neurodegeneration [3] and it is apparent from studies of neuronal cultures that Aβ mediated cell death [4], only occurs if cells re-entry into a mitotic state [5]. The post-mitotic, quiescent state of adult neurons is long standing dogma in neuroscience. However, there is accumulating evidence that neurons re-enter the cell division cycle in AD [4, 6-18]. In mammalian cells, this mitotic re-entry depends on extracellular signals, namely on the balance between mitogenic stimuli and differentiating factors [4,19,20]. Sequential expression, activation and degradation of cyclin/Cyclin Dependent Kinase (CDK) complexes drive the cell cycle, and their regulation is achieved via mechanisms of transcription, phosphorylation, proteolysis, and association with CDK Inhibitors (CDKI) [21]. G0/G1 phase transfer in the cell cycle is triggered by the presence of cyclin D/Cdk4 and Cdk6 complex [22]. When DNA replication is completed, the cyclin A/Cdk2 complex enables transition from the S to the G2 phase (S/G2) of the cell cycle. For the cell to enter the G2 phase of mitosis (G2/M), degradation of cyclin A/Cdk 2 complex and expression of cyclin B which activates Cdk2 must take place [22]. Two major observations have helped establish the cell cycle hypothesis for AD neurodegeneration. First, activation of cell cycle regulators generally precedes formation of degenerative lesions such as NFTs, and the regulators and downstream effectors eventually become incorporated into NFTs [23]. Therefore, it has been postulated that cell-cycle regulators initiate and mediate the neurodegenerative process . Second, with the exception of karyokinesis and cytokinesis, markers from every phase of the cell cycle, early and late phase (metaphase-anaphase transition) which are consequently presented by duplicated chromosomes (tetraploidy) [24-27], aneuploidy [27-35], bi-nuclear cells [36] and Premature Centromere Division (PCD) [37] have been found in degenerating neurons (Table 1). The present phenotypes represent a cell ahead of the S phase. Still, the AD cell goes into a G2/M block and eventually dies through the process of apoptosis. Except for chromosome 21 that has been found to be aneuplodogenic and in a tetraploidy state in neurons affected by AD [24-35], chromosome X has been recently reported to show instability reported as aneuploidy [38] and skewing [39]. Both, aneuploidy and skewing are related to the centromere instability phenotype, or PCD [37] (Table 1).