A common biological mechanism in cancer and Alzheimer's disease?

Abstract

Cancer and Alzheimer's disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Abeta) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to "repair and live"- or "die" could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer.

Figure 1

Role of p53 in cancer and AD. In response to toxic or stress signals, p53 is activated through a number of post-translational modifications and induces cell cycle arrest among other functions. The decision is made whether to induce DNA repair or apoptosis of damaged cells to maintain genomic stability. If the cell machinery in the whole organism were shifted to high p53 in response to stressors, the cells would be more prone to cell death and AD could develop. If, on the contrary, the cell machinery were shifted to low or no p53, the cells would be more prone to develop a cancer. ROS, reactive oxygen species.

Figure 2

The wnt signaling pathway involvement in cancer and neurodegeneration. When wnt binds to the LRP-frizzled receptor in the surface of the cell,β-catenin is stabilized promoting expression of wnt target genes and proliferation. Subtle disequilibrium in any step of the pathway in a manner that determines activation of the pathway, such as increased expression or polimorphisms that induce activation of wnt or β-catenin would favor cancer development, preventing neurodegeneration. On the contrary, conditions that induce inactivation of the pathway would favor the development of Alzheimer’s disease or other degenerative disorder, and as a consequence protect from cancer development.