The DNA Replication Stress Hypothesis of Alzheimer’s Disease

Figure 1

Simplified schematic presentation of the cell cycle theory of AD. Quiescent neuronal cells (G0 phase) demonstrate the cell cycle reactivation by either endogenous or environmental mitogenic stimuli followed by reentry into the G1 phase. The G0/G1 phase transition is critical for a postmitotic neuron and potentially causes neuronal cell death. During G1 phase, diploid neurons (chromosomal complement: 2N; number of chromosomes: 46; DNA content: 2C) demonstrate G1-specific cell cycle markers (cyclin D and CDK4/6 complex, cyclin E and CDK2 complex) which are involved in the regulation of G1 phase progression. Cells successfully passing G1 enter the S phase (phase of DNA replication). During the S phase, CDK2/cyclin E should be silenced to repress additional round of replication of genomic DNA. Protein markers of the S phase are A-type cyclins (cyclin A/CDK2 complex). This complex is essential for proper completion of S phase and transition from S to G2 phase. DNA content of cells during S phase changes from 2C to 4C (chromosome number is still 2N, but DNA content after replication is tetraploid). During G2 phase, cyclin A is degraded and cyclin B/CDC2 complex (protein biomarker of late S/early G2 phases) is formed. Cyclin B/CDC2 complex is essential for triggering mitosis. Neuronal cells in G2 phase demonstrate tetraploid (4N) DNA content or, more precisely, possess a nucleus with 46 replicated chromosomes. Chromosomal complement (genomic content) of cells in G2 consists of one set of 46 duplicated chromosomes (DNA content: 4N or 4C: diploid nucleus with replicated chromosomes, for more details see [20]), each having two chromatids—“mitotic” tetraploidy. It is to note that true constitutional polyploidy is a term used to describe cell containing more than two homologous sets of chromosomes (4N or 92 chromosomes, DNA content: 4C). We suggest that postmitotic neurons are able to replicate DNA but are not able to make a G2/M transition and divide into two daughter cells.