Alzheimer's Disease and Cancer: When Two Monsters Cannot Be Together

Abstract

Alzheimer's disease (AD) and cancer are among the leading causes of human death around the world. While neurodegeneration is the main feature of AD, the most important characteristic of malignant tumors is cell proliferation, placing these two diseases in opposite sides of cell division spectrum. Interestingly, AD and cancer's pathologies consist of a remarkable common feature and that is the presence of active cell cycle in both conditions. In an in vitro model of primary adult neuronal culture, we previously showed that treating cell with beta amyloid forced neurons to start a cell cycle. Instead of cell division, however, neuronal cell cycle was aborted and a massive neurodegeneration was left behind as the consequence. A high level of cell cycle entry, which is a requirement for cancer pathogenesis, was reported in clinically diagnosed cases of AD, leading to neurodegeneration. The diverse clinical manifestation of a similar etiology, have puzzled researchers for many years. In fact, the evidence showed an inverse association between AD and cancer prevalence, suggesting that switching pathogenesis toward AD protects patients against cancer and vice versa. In this mini review, we discussed the possibility of involvement of cell proliferation and survival dysregulation as the underlying mechanism of neurodegeneration in AD, and the leading event to develop both disorders' pathology. As examples, the role of phosphoinositide 3 kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway in cell cycle re-entry and blocking autophagy are discussed as potential common intracellular components between AD and cancer pathogenesis, with diverse clinical diagnosis.

Keywords: Alzheimer’s disease; PI3K/Akt/mTOR; autophagy; beta amyloid; cancer; cell cycle; neurodegeneration; tau phosphorylation.

FIGURE 1

PI3K/Akt/mTOR role in AD development and neurodegeneration through cell cycle activation and autophagy inhibition. Cell stress such as growth factor deprivation or metabolic and oxidative stress enhance PI3K/Akt activity. Akt activation increases Cyclin D1 activity directly or via mTOR activation, while mTOR also activates cdk4. Together enhanced activity of cyclin D1 and cdk4, restart a cell cycle, forcing the neuron to leave G0 and enter G1 phase. Consequent activation of cell cycle kinases, increases APP phosphorylation (cdk2, cdk4, cdk5) toward producing higher amount of Aβ, while activated caspases during cell cycle increase APP proteolysis. Together, increasing in APP phosphorylation and proteolysis lead to higher production and excretion of Aβ, along with high level of phosphorylated tau due to tau kinase activity of cdk2 and cdk5. Activated mTOR also contributes to Aβ accumulation and plaque formation by blocking autophagy and reducing Aβ clearance.

FIGURE 2

The period of metabolic stress, defines the fate between cancer and AD. (A) High metabolic demand of cancerous tissue high jacks energy from highly energy demanded neurons. Acute condition of inadequate supply of energy and concurrent oxidative stress activates AMPK, leading to FOXO activation and m-TOR inhibition. A bust in antioxidant defense occurs along with blocking cell cycle re-entry due to FOXO activation and mTOR inhibition, respectively, which reduces the risk of AD development. (B) In the absence of cancer, the acute signal to boost the antioxidant defense of neurons does not exist. Instead, due to aging the neurons, which are facing mitochondrial aging, experience a chronic oxidative stress. This is due to chronic effect of energy stress and accumulation of oxidative damage. Activation of PI3K/Akt pathways dominantly occurs as a protective response, however, this activation leads to further FOXO inhibition and m-TOR activation. Consequently, cell cycle re-entry along with reduced expression of antioxidant enzymes result in progressing of AD pathology.

FIGURE 3

Diagram of the phosphatidylinositol 3 kinase/Akt/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and cell cycle and autophagy dysregulation in cancer and Alzheimer’s disease (AD). Mitochondrial stress, a common event in AD and cancer activates PI3K/AKT/mTOR pathway. Activated mTOR, promotes cell cycle re-entry and inhibits autophagy. Cell cycle re-entry contributes in cellular over proliferation, with the higher chance of DNA damage as a result, in cancer. Cell cycle could not be completed by mature neurons and will result in neuronal death (neurodegeneration), and AD hallmarks development (beta amyloid (Aβ) and hyperphosphorylated tau) while the neurons are remained in G2 phase of cell cycle, before death. Inhibition of autophagy due to mTOR activation also participates in AD and cancer pathogenesis.