Preclinical and Clinical Early Alzheimer's Disease (AD) Biomarker Discovery Using Proteins and MicroRNAs Carried by Small Extracellular Vesicles (sEVs)

Moradi Bachiller, Soraya (2021). Preclinical and Clinical Early Alzheimer's Disease (AD) Biomarker Discovery Using Proteins and MicroRNAs Carried by Small Extracellular Vesicles (sEVs). PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0001289b

Abstract

Alzheimer’s disease (AD) begins several years before the onset of symptoms. Unfortunately, current therapies treat too late and have limited efficacy.

To improve this, clinical trials need to test a potential drug earlier in the disease progression by increasing the diagnostic accuracy of an early or even asymptomatic stage for which reliable and minimally invasive biomarkers are mandatory.

In the context of blood-based biomarker discovery for early dementia, we focused on small extracellular vesicles (sEVs). SEVs contain specific cargoes that may reflect brain disease. They can cross the blood-brain barrier and can be isolated from biofluids, which may improve the detection of AD outside the brain.

Therefore, we investigated NFL, TREM2, and a possible novel AD candidate called ECSIT in mouse and human plasma-sEVs.

We found that TREM2, ECSIT and NFL are carried in mouse and human sEVs. Surprisingly, ECSIT showed lower levels in subjects with cognitive deficits, suggesting the possible role of this protein as sEVs-candidate biomarker for the early stage of AD, and prompting us to study its role in a cellular model for AD, where we found a possible link between ECSIT and APP.

We also focused on a different approach to reveal the presence of dysregulated microRNAs in human plasma-sEVs across AD stages.

To pursue this aim, we compared sEV-microRNA content from cognitively normal controls (Ctrl), mild cognitive impaired (MCI) and demented (AD) subjects. We showed a great number of dysregulated miRNAs in the AD stage. However, we were unable to detect them for the MCI stage.

We conclude that our research contributed to assess the importance of plasma-sEVs as biomarker source and provided insights in the field of blood-based biomarker discovery for AD, that, we hope, may help to increase the diagnostic accuracy of the early stage of dementia, thus, enabling drug discovery progress.

Viewing alternatives

Metrics

Public Attention

Altmetrics from Altmetric

Number of Citations

Citations from Dimensions

Item Actions

Export

About

Recommendations