The Role of Exosomes as Mediators of Neuroinflammation in the Pathogenesis and Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive dementia. Accumulation of β-amyloid peptide 1-42 and phosphorylation of tau protein in the brain are the two main pathological features of AD. However, comprehensive studies have shown that neuroinflammation also plays a crucial role in the pathogenesis of AD. Neuroinflammation is associated with neuronal death and abnormal protein aggregation and promotes the pathological process of β-amyloid peptide 1-42 and tau protein. The inflammatory components associated with AD include glial cells, complement system, cytokines and chemokines. In recent years, some researchers have focused on exosomes, a type of membrane nano vesicles. Exosomes can transport proteins, lipids, microRNAs and other signaling molecules to participate in a variety of signaling pathways for signal transmission or immune response, affecting the activity of target cells and participating in important pathophysiological processes. Therefore, exosomes play an essential role in intercellular communication and may mediate neuroinflammation to promote the development of AD. This paper reviews the occurrence and development of neuroinflammation and exosomes in AD, providing a deeper understanding of the pathogenesis of AD. Furthermore, the role of exosomes in the pathogenesis and treatment of AD is further described, demonstrating their potential as therapeutic targets for neuroinflammation and AD in the future.

Keywords: Alzheimer’s disease; beta-amyloid; exosomes; neuroglia; neuroinflammation; tau; therapeutic target.

FIGURE 1

Composition of exosomes. Exosomes are lipid bilayer vesicles with a diameter of 30–150 nm, which can carry specific proteins, lipids, mRNA, miRNA and other substances. In addition, exosome membrane is rich in lipid rafts (cholesterol, sphingolipids, ceramide and glycerophospholipids). Exosome proteins include four transmembrane proteins (CD9, CD63, CD81, CD82), heat shock proteins (HSC70, HSP60, Hsp70, Hsp90), proteins involved in MVB processing (Alix, TSG101), cytoskeleton proteins (actin, tubulin, cofilin, profilin, fibronectin, etc.), fusion/transport proteins (Annexins, Rabs), integrins, signal transduction proteins, immune regulatory molecules (MHC I and II) and various metabolic enzymes. MHC, major histocompatibility complex; mRNA, messenger RNA; miRNA, microRNA; MVB, multivesicular body.

FIGURE 2

Roles of exosomes in the healthy brain and a neuroinflammatory state of AD. (A) Healthy brain. Exosomes mediate normal intercellular communication in the brain. Glial-derived exosomes mediate important functions participating in neural circuit development and maintenance, promoting neurite outgrowth, synaptic activity and neuronal survival. Oligodendrocytes-derived exosomes provide trophic support to axons facilitating myelination. (B) Neuroinflammatory state of AD. In Alzheimer’s disease (AD), as an inflammatory mediator, exosomes induce neuroinflammation through information exchange between neurons and glial cells. They can diffuse in interconnected neurons and transport amyloid-beta (Aβ) and tau proteins through the endosomatic pathway and axonal transport. At the same time, exosomes can cause neurological dysfunction by carrying pathogenic substances such as malregulated miRNA, mRNA and proteins. These exosomes are able to cross the blood-brain barrier propagating the neuroinflammatory response to the periphery. Similarly, plasma exosomes can also enter the brain and target neurons and glial cells, causing a series of pathophysiological reactions.