The role of autophagy in brain health and disease: Insights into exosome and autophagy interactions

Abstract

Effective management of cellular components is essential for maintaining brain health, and studies have identified several crucial biological processes in the brain. Among these, autophagy and the role of exosomes in cellular communication are critical for brain health and disease. The interaction between autophagy and exosomes in the nervous system, as well as their contributions to brain damage, have garnered significant attention. This review summarizes that exosomes and their cargoes have been implicated in the autophagy process in the pathophysiology of nervous system diseases. Furthermore, the onset and progression of neurological disorders may be affected by autophagy regulation of the secretion and release of exosomes. These findings may provide new insights into the potential mechanism by which autophagy mediates different exosome secretion and release, as well as the valuable biomedical applications of exosomes in the prevention and treatment of various brain diseases by targeting autophagy.

Keywords: Autophagy; Brain; Brain disease; Exosomes; Nervous system.

Fig. 1

The brief molecular mechanisms of the autophagy signaling pathway. Internal and external signals stimulate the mTOR and AMPK. mTOR inhibits the autophagy initiation complex, ULK complex, consisting of ULK1/2, ATG13, FIP200 and ATG 101a. Additionally, AMPK activation leads to ULK1 phosphorylation, promoting the assembly of the ULK complex. The ULK complex further phosphorylates Beclin1, promoting formation of the VPS34 complex, which initiates autophagy of pre-phagophore. The isolation membrane, or phagophore, is promoted by a series of enzymatic reactions involving ATG proteins and incorporation of ATG homologs (for example, LC3) into the growing membrane. After cargo selection, the maturated autophagosome fuse with lysosome to degrade the cargos by acid hydrolases in lysosomes and then released the nutrients and metabolites to the cytoplasm.

Fig. 2

Autophagy in cells of brain. Schematic depicting autophagy in neurons, astrocytes, microglia and neurovascular. In neurons, autophagosomes can form locally within the soma or originate in the distal axon and then travel to the soma. In latter case, autophagosomes fuse with late endosomes in the distal axon following formation, then travel toward the proximal axon and soma and can migrate into dendrites to facilitate post-synaptic functions.

Fig. 3

Exosomes affect brain function and interact with autophagy Exosomes can regulate inflammation, affect neurostructural integrity affect the integrity of the blood-brain barrier and inhibit apoptosis in brain. There exists cross-regulation of exosomes and autophagy in brain. Various exosomal contents or composition (MicroRNA, crcRNA, protein, Long non-coding RNA and et al.) can act on different autophagy factors (LC3, Beclin-1, p53, p62 and et al.), inducing or inhibiting autophagy process. Autophagy can affect the formation, removal, transmission and release of exosomes in the brain.