Exploring the bi-directional relationship between autophagy and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) deposition and Tau phosphorylation, in which its pathogenesis has not been cleared so far. The metabolism of Aβ and Tau is critically affected by the autophagy. Abnormal autophagy is thought to be involved in the pathogenesis of AD, regulating autophagy may become a new strategy for AD treatment. In the early stage of AD, the presence of Aβ and Tau can induce autophagy to promote their clearance by means of mTOR-dependent and independent manners. As AD progress, the autophagy goes aberrant. As a result, Aβ and Tau generate continually, which aggravates both autophagy dysfunction and AD. Besides, several related genes and proteins of AD can also adapt autophagy to make an effect on the AD development. There seems to be a bi-directional relationship between AD pathology and autophagy. At present, this article reviews this relationship from these aspects: (a) the signaling pathways of regulating autophagy; (b) the relationships between the autophagy and the processing of Aβ; (c) Aβ and Tau cause autophagy dysfunction; (d) normal autophagy promotes the clearance of Aβ and Tau; (e) the relationships between the autophagy and both genes and proteins related to AD: TFEB, miRNAs, Beclin-1, Presenilin, and Nrf2; and (f) the small molecules regulating autophagy on AD therapy. All of the above may help to further elucidate the pathogenesis of AD and provide a theoretical basis for clinical treatment of AD.

Keywords: Alzheimer's disease; Tau; autophagy; genes and proteins; β-amyloid.

Figure 1

The signaling transduction pathways of regulating autophagy. The autophagy can be regulated by two pathways: mTOR‐dependent pathway and mTOR‐independent pathway. The mTOR is the core molecule in regulating autophagy, and phosphorylation of mTOR can lead to the phosphorylation of P70S6K1 which is a subtrate protein of mTOR, thereby inhibiting autophagy. In a physiological situation, the autophagy can be activated by some factors such as chronic stress, starvation, and GCs via inhibiting the expression of mTOR. The PI3K/Akt/mTOR and TRPML1/PPARγ/AMPK/mTOR are negnative and positive pathways in regulating autophagy respectively, inhibition and activation of the two pathways can activate autophagy. Besides, the Dihydroceramide is a newly positive regulator of autophagy via mTOR. ROS induces autophagy through both mTOR‐dependent and independent pathways. The inflammatory activation of microglia also plays a role in activating autophagy. Others, the TyrRS/PARP1/SIRT1 and TRPM7/CaMKKβ/AMPK are two positive pathways in regulating autophagy

Figure 2

The related miRNAs and target genes/pathways that regulate autophagy. The miRNAs expression altered in AD patients and animal models. MiR‐124 inhibited abnormal autophagy via BACE1‐regulated autophagy pathway ameliorating AD pathology; miR‐214‐3p and miR‐299‐5p ameliorated cognitive deficit by negatively and respectively targeting the expression of Atg12 and Atg5 in AD mice; miR132/212 also associated with autophagy dysfunction by targeting the expression of Atg9a and Atg5‐12; miR‐34a regulated autophagy through SIRT1/mTOR pathway. The autophagy also be regulated by miR‐101a via the MAPK pathway. Finally, miR‐96 could regulate autophagy through the mTOR pathway to mediate the role of chronic cerebral hypoperfusion in the pathogenesis of AD