Extracellular Vesicles in Alzheimer's and Parkinson's Disease: Small Entities with Large Consequences

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases.

Keywords: Alzheimer’s disease; Parkinson’s disease; biomarkers; extracellular vesicles.

Figure 1

The role of multivesicular bodies (MVBs) and extracellular vesicles (EVs) in amyloid precursor protein (APP) processing. APP is synthesized in the endoplasmic reticulum (ER) and subsequently transported through the Golgi compartment to early endosomes (1) or the plasma membrane (2), where it can be cleaved by α-secretase in the non-amyloidogenic pathway. This cleavage leads to the formation of soluble APP α (sAPPα) and the α-C-terminal fragment (α-CTF or C83). Alternatively, APP can be re-internalized in endosomes (3) where the amyloidogenic cleavage by β-secretase preferentially occurs. Thereby, sAPPβ and β-CTF (C99) are generated. The formation of the APP intracellular domain (AICD) and either the P3 fragment or the amyloid β (Aβ) peptide from α- and β-CTF, respectively, requires cleavage by the γ-secretase complex. Early endosomes recycle to the plasma membrane (4), undergo retrograde transport to the trans-Golgi network (5) or mature into late endosomes/MVBs (6). The latter either fuse with lysosomes (7) or with the plasma membrane (8), resulting in the extracellular release of their intraluminal vesicles (ILVs) as EVs. Several products of the APP processing pathway have been localized to MVBs (i.e., APP itself; α- and β- CTF; AICD; Aβ) and EVs (i.e., APP itself; α- and β- CTF; Aβ; α-, β- and components of the γ-secretase complex), whereby Aβ can be localized both on the inside and on the surface of EVs. Figure created with BioRender.