The role of mTOR signaling in Alzheimer disease

Abstract

The buildup of Abeta and tau is believed to directly cause or contribute to the progressive cognitive deficits characteristic of Alzheimer disease. However, the molecular pathways linking Abeta and tau accumulation to learning and memory deficits remain elusive. There is growing evidence that soluble forms of Abeta and tau can obstruct learning and memory by interfering with several signaling cascades. In this review, I will present data showing that the mammalian target of rapamycin (mTOR) may play a role in Abeta and tau induced neurodegeneration.

Figure 1

Schematic representation of the involvement of mTOR in AD. In a healthy neuron, mTOR activity is tightly regulated and basal autophagy levels are sufficient to remove Aβ and tau. During early stages AD, an increase in soluble Aβ levels leads to mTOR hyperactivity, which in turn will reduce autophagy induction (represented in the diagram by a reduction in autophagosomes). Lower autophagy function will eventually lead to an increase in the steady-state levels of Aβ and tau. Notably, high Aβ levels will further increase mTOR activity thus creating a vicious cycle that ultimately will promote higher Aβ levels. Increasing autophagy induction in early-AD may represent a valid therapeutic approach as it will facilitate autophagosome formation and thus remove Aβ and tau. During late stages AD, there is evidence that autophagosomes fail to fuse with lysosomes. It is anticipated that increasing autophagy induction in late stages AD may further clog the cells by generating more autophagosomes that will not be cleared, although this has not been directly tested.