Exosome-Mediated Mitochondrial Regulation: A Promising Therapeutic Tool for Alzheimer's Disease and Parkinson's Disease

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are representative neurodegenerative diseases with abnormal energy metabolism and altered distribution and deformation of mitochondria within neurons, particularly in brain regions such as the hippocampus and substantia nigra. Neurons have high energy demands; thus, maintaining a healthy mitochondrial population is important for their biological function. Recently, exosomes have been reported to have mitochondrial regulatory potential and antineurodegenerative properties. This review presents the mitochondrial abnormalities in brain cells associated with AD and PD and the potential of exosomes to treat these diseases. Specifically, it recapitulates research on the molecular mechanisms whereby exosomes regulate mitochondrial biogenesis, fusion/fission dynamics, mitochondrial transport, and mitophagy. Furthermore, this review discusses exosome-triggered signaling pathways that regulate nuclear factor (erythroid-derived 2)-like 2-dependent mitochondrial antioxidation and hypoxia inducible factor 1α-dependent metabolic reprogramming. In summary, this review aims to provide a profound understanding of the regulatory effect of exosomes on mitochondrial function in neurons and to propose exosome-mediated mitochondrial regulation as a promising strategy for AD and PD.

Keywords: Alzheimer’s disease; Parkinson’s disease; exosome; mitochondria; neurodegenerative disease.

Graphical abstract

Figure 1

Illustration showing the effect of molecules delivered by exosomes on mitochondrial biosynthesis in neurons. STIMATE, TFAM mRNA, SIRT1, and various factors delivered via exosomes upregulate PGC1α/NRF1/TFAM signaling. Exosomes also transfer other factors that downregulate miR-30e-5p, which inhibits PGC1α signaling.

Figure 2

Illustration showing the way molecules delivered by exosomes regulate mitochondrial dynamics in neurons. In neurons, the balance between mitochondrial fusion and fission is important for MQC. Nrf2 delivered via exosomes inactivates Drp1, thereby reducing excessive mitochondrial fission. In addition, delivery of factors regulating the expression or transfer of Miro1 via exosomes are expected to transport healthy mitochondria to deteriorated neurons.

Figure 3

Illustration showing that molecules delivered by exosomes regulate mitophagy in neurons. Numerous activators delivered by exosomes, such as BNIP3, miR-138-5p, and miR-let-7e, each send signals that ultimately increase mitophagy. However, epicatechin gallate delivered via exosomes alleviated the excessive apoptosis observed in neurodegenerative diseases.