Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Abstract

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated. Hence, we performed a thorough review by summarizing the physiological roles of these key cancer-related signaling pathways in AD pathogenesis, comprising of the crosstalk of these pathways with neurofibrillary tangle and senile plaque formation to impact AD phenotypes. Importantly, the pharmaceutical investigations of anti-aging and AD relevant medications have also been highlighted. In summary, in this review, we discuss the potential role that cancer-related signaling pathways may play in governing the pathogenesis of AD, as well as their potential as future targeted strategies to delay or prevent aging-related diseases and combating AD.

Keywords: Aging; Alzheimer's disease; Amyloid; Cell signaling; Tau; Tumorigenesis.

Figure 1

The protective role of autophagy pathway in AD pathogenesis. Where indicated, red arrow indicates positive regulation and black line means negative regulation.

Figure 2

The protective role of the FOXO pathway in aging and AD pathogenesis. Briefly, FOXO could be phosphorylated by distinct kinase(s), acetylated or de-acetylated by SIRT and p300, respectively. Where indicated, red arrow indicates positive regulation and black line implicates negative regulation.

Figure 3

The role of the IR/Akt/mTOR signaling pathway in promoting aging and AD pathogenesis. Briefly, Akt kinase could phosphorylate or regulate many downstream substrates including GSK3, FOXO, GLUT and mTOR to manipulate metabolic and protein homeostasis as well as autophagy. Where indicated, red arrow indicates positive regulation and black line suggests negative regulation.

Figure 4

The protective role of the SIRT pathway in aging and AD pathogenesis. Briefly, low energy-induced SIRT could deacetylate various downstream transcriptional factors including PGC1, FOXO, p53 or p65 to govern the biological processes including autophagy and apoptosis. Where indicated, red arrow indicates positive regulation, and black line suggests negative regulation.

Figure 5

The controversial role of the hypoxia/HIF signaling pathway in aging and AD pathogenesis. Briefly, the HIF transcription factors induce angiogenesis to inhibit the brain injury. At the same time, HIF could promote BACE1 to enhance Aβ and contribute to AD. Where indicated, red arrow indicates positive regulation and black line suggests negative regulation.

Figure 6

The role of the ROS pathway in aging and AD pathogenesis. Briefly, different stress-induced ROS, which could subsequently regulate multiple kinases and transcriptional factors to contribute aging and AD pathogenesis. Where indicated, red arrow indicates positive regulation and black line suggests negative regulation.

Figure 7

The protective role of the AMPK pathway in aging and AD pathogenesis. Where indicated, red arrow indicates positive regulation and black line suggests negative regulation.

Figure 8

Major cancer-related signaling pathways that confer to aging and AD pathogenesis, and potential inhibitors that could be used for aging/AD intervention. Where indicated, red arrow indicates positive regulation and black line suggests negative regulation.