Exosomes as Biomarkers for Neurodegenerative Disorders

Neural Regeneration Research. 2024 Jan; 19 (1): 75-79.

Authors: Huber CC, Wang H.

INTRODUCTION

Accumulating evidence supports that the exosomes derived from the neurons of neurodegenerative disease patients could amplify the progression of neurodegenerative disorders by delivering their contents to recipient cells. Delivering their content to recipient cells alters the recipient cells' function. Moreover, due to exosomal content reflecting their parental cell, exosomes make an attractive biomarker for clinical diagnostics. As the parental cell undergoes changes associated with the neurodegenerative disorder, the content of exosomes will reflect those changes. Exosomes can be easily isolated from patients in a non-invasive way from biological fluids, and any change in exosomal content can be monitored. Changes in exosomal content may serve as early biomarkers for diagnosing neurodegenerative diseases.

Fig. 1 Exosomes serve as biomarkers for neurodegenerative diseases.

Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder projected to impact an estimated 14 million people in the United States by 2050. AD is characterized by the accumulation of extracellular amyloid-β (Aβ) and intracellular accumulation of hyperphosphorylated tau.
The amyloid precursor protein (APP) can be cleaved by two pathways: non-amyloidogenic and amyloidogenic processing pathways. In the non-amyloidogenic pathway, APP is cleaved by α- and γ-secretase to produce C-terminal fragments and a secreted form of APP. These products have been shown to have neuroprotective effects on the cell. In the amyloidogenic pathway, APP is cleaved by β- and γ-secretase to generate Aβ peptides of various lengths.
Previous studies have shown that oligomeric Aβ is increased in exosomes isolated from AD brain samples. Further, intracellular oligomeric Aβ co-localizes with exosomes, and these exosomes facilitate the propagation of oligomeric Aβ between neurons. There is a correlation between Aβ_1-42, phosphor-T181-tau, and phosphor-S386-tau in exosomes with AD progress. Furthermore, the levels of these proteins in exosomes can accurately predict the conversion of mild cognitive impairment to AD.

Parkinson's Disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder projected to impact 12 million people by 2040. The disease is characterized by the loss of dopamine-producing neurons in the midbrain and the formation of Lewy bodies made up of the α-synuclein protein.
Previous studies have shown that exosomes isolated from the serum of PD patients contain α-synuclein, and mild to late-stage PD patients contain the highest amounts of exosomal α-synuclein. The data suggest that α-synuclein in plasma neuronal exosomes is a biomarker for Parkinson's disease development and progression.
Recently, the propagation of α-synuclein between cells was thought to be mediated at least partially by exosomes. In the cerebrospinal fluid, lower levels of α-synuclein have been reported in PD patients compared to control individuals. In contrast, the plasma exosomal α-synuclein levels are significantly higher in PD patients, highlighting the role of exosomes in serving as a biomarker for diagnosing PD.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder projected to continually increase in prevalence in the coming years. ALS results in the loss of motor neurons causing individuals to experience muscle weakness, atrophy, and death after a few years of disease onset. Mutations in SOD1, an enzyme called Cu-Zn superoxide dismutase responsible for converting superoxide to hydrogen peroxide or oxygen, are attributed to causing ALS. In addition, mutations in TARDBP that encode the protein TDP-43 function as a DNA/RNA binding protein have also been shown to be a hallmark of ALS pathophysiology.

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