The DNA Replication Stress Hypothesis of Alzheimer’s Disease

Figure 2

The DNA replication stress hypothesis of AD. Interplay between essential elements of the AD-type dementia pathogenetic cascade is proposed. The genetic influences (PSEN or APP mutations, trisomy 21, APOE4 genotype), metabolic changes, and environmental factors affecting neuronal homeostasis in the aging brain lead to activation of neuronal proliferation. Mitogens, which do exist in the human brain (neuronal cells), induce additional stimuli of extensive adult neurogenesis in the hippocampus. In the AD brain, such events would lead to increased hippocampal neurogenesis. A side effect could be that these mitogenic stimuli activate cell cycle reentry in postmitotic neurons. The latter is a pathological activation of neuronal cell cycle, including reentry into G1 and S phases and initiation of DNA replication. Neurons showing protein markers of G2/M phase, probably, contain chromosome set of 23 duplicated chromosome pairs with unseparated chromatids (DNA content—4C; chromosome complement: 2N) and become tetraploid in a sense of DNA content (4C). According to the commonly accepted theory of neuronal cell cycle reentry and death, some neuronal populations complete the DNA synthesis but are arrested during the G2/M transition. Therefore, neuronal death occurs in G2 phase. Alternatively, one can propose that a large proportion of activated postmitotic neurons in the AD brain are unable to pass properly the S phase. This would lead to accumulation of genomic and chromosomal instabilities throughout ontogeny (DNA breaks, aneuploidy). In addition, replication-induced DNA damages would lead to fork stalling, incomplete or inefficient DNA replication, together designated as replication stress. Replication stress may be considered the leading cause of neuronal cell death due to processing into S phase or accumulation of genetic instabilities, which together constitute an important element of the AD pathogenetic cascade. According to the present hypothesis, the possibility to link the two main pathways of AD arises from the introduction of accumulation of genomic instabilities associated with DNA replication stress, which is able to produce as neuronal cell death (replicative cell death) as chromosomal aneuploidy due to natural selection in neural cell populations probably causing extra APP in the diseased brain.