Exosome Determinants of Physiological Aging and Age-Related Neurodegenerative Diseases

Abstract

Aging is consistently reported as the most important independent risk factor for neurodegenerative diseases. As life expectancy has significantly increased during the last decades, neurodegenerative diseases became one of the most critical public health problem in our society. The most investigated neurodegenerative diseases during aging are Alzheimer disease (AD), Frontotemporal Dementia (FTD) and Parkinson disease (PD). The search for biomarkers has been focused so far on cerebrospinal fluid (CSF) and blood. Recently, exosomes emerged as novel biological source with increasing interest for age-related neurodegenerative disease biomarkers. Exosomes are tiny Extracellular vesicles (EVs; 30-100 nm in size) released by all cell types which originate from the endosomal compartment. They constitute important vesicles for the release and transfer of multiple (signaling, toxic, and regulatory) molecules among cells. Initially considered with merely waste disposal function, instead exosomes have been recently recognized as fundamental mediators of intercellular communication. They can move from the site of release by diffusion and be retrieved in several body fluids, where they may dynamically reflect pathological changes of cells present in inaccessible sites such as the brain. Multiple evidence has implicated exosomes in age-associated neurodegenerative processes, which lead to cognitive impairment in later life. Critically, consolidated evidence indicates that pathological protein aggregates, including Aβ, tau, and α-synuclein are released from brain cells in association with exosomes. Importantly, exosomes act as vehicles between cells not only of proteins but also of nucleic acids [DNA, mRNA transcripts, miRNA, and non-coding RNAs (ncRNAs)] thus potentially influencing gene expression in target cells. In this framework, exosomes could contribute to elucidate the molecular mechanisms underneath neurodegenerative diseases and could represent a promising source of biomarkers. Despite the involvement of exosomes in age-associated neurodegeneration, the study of exosomes and their genetic cargo in physiological aging and in neurodegenerative diseases is still in its infancy. Here, we review, the current knowledge on protein and ncRNAs cargo of exosomes in normal aging and in age-related neurodegenerative diseases.

Keywords: Alzheimer’s disease; Parkinson’s disease; aging; exosomes; frontotemporal dementia; non-coding RNA.

Figure 1

Interaction mechanisms between exosome and recipient cell. Exosomes secreted from a donor cell can move through biological fluids to reach the recipient cell close or distant to the site of their origin. The interaction mechanisms with recipient cell are various: (1) membrane fusion with transfer of exosomal cargo to recipient cell; (2) internalization of whole exosome by endocytosis and release of the cargo by fusion with endosomal membrane; (3) activation of signaling pathways through ligand/receptor interaction. For more details, see review by Jan et al. (2017, 2019).

Figure 2

(A) Exosome structure and cargo. Exosomes are surrounded by a phospholipid bilayer and their content reflects the cell of origin. So besides to generic molecules that identify all exosomes as Tetraspanins, Lipid rafts, MVB formation proteins, membrane transport and fusion proteins, there are other molecules specific to their origin, as L1CAM for neural exosomes as well as proteins related to aging and neurological diseases such as β-amyloid, p-Tau, LRKK2, insulin receptor substrate 1 (IRS-1), a-synuclein, amyloid precursor protein (APP), TDP-43, depeptide protein repeats (DPRs) and many others. In addition, there is also a nucleic component consisting of DNA, mRNA and different kinds of non-coding RNAs (ncRNAs; miRNAs, lncRNAs, circRNAs, piwi-RNA, etc…). (B) Exosomes: a double-edged sword in neurodegenerative disease. Exosomes could favorite and/or trigger the spreading of the disease leading to neurodegeneration or they could sequester neuro-toxic components from neural cells protecting them.

Figure 3

Exosomes are able to pass through blood brain barrier (BBB) in both directions. This means that specific exosomes (i.e., the neural ones with L1CAM on their surface) detected in the cerebrospinal fluid (CSF) can be released into bloodstream and vice versa. This feature makes exosomes appealing in the research of new sources of biomarkers suitable for use in clinical practice, as liquid biopsy that could replace current invasive diagnostic methods.

Figure 4

Comprehensive expression profile patterns of ncRNAs differentially expressed in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Parkinson’s disease (PD) extracted from serum or CSF exosomes.