APOE3-Christchurch Extracellular Vesicles in the Preclinical Stage of Familial Alzheimer’s Disease
Year: 2025
Type: dissertation
Study design: Observational Study
Abstract: The PSEN1E280A mutation, which causes autosomal dominant Alzheimer’s disease (ADAD), is characterized by a predictable age of onset, providing a valuable model to investigate the earliest stages of Alzheimer’s pathology. While classical neuropathological markers such as β-amyloid and p-tau are well established, the peripheral biological changes occurring during the preclinical stage, beyond these traditional markers, remain poorly understood. In this context, extracellular vesicles (EVs) have emerged as promising peripheral indicators of disease-related molecular progression. The APOE3 Christchurch (APOE3Ch) variant, which has been shown to delay symptom onset in PSEN1E280A carriers, offers a unique model to explore peripheral mechanisms of protection, though its impact on EV profiles remains unknown. Whether EVs can exhibit early peripheral signatures of vulnerability or resistance to ADAD remains an open question. To address this, we isolated plasma EVs from five participant groups: cognitively unimpaired controls (CNT, n = 10) were included as a reference group. These subjects were confirmed to be non-carriers of the PSEN1E280A mutation, although their APOE genotype was not available; APOE3Ch carriers without the PSEN1E280A mutation (APOE3Ch, n = 10); PSEN1E280A carriers with mild cognitive impairment (MCI PSEN1E280A-APOE3, n = 10); cognitively unimpaired PSEN1E280A carriers with APOE3 (non-MCI PSEN1E280A-APOE3, n = 10); and cognitively unimpaired PSEN1E280A carriers with APOE3Ch (non-MCI PSEN1E280A-APOE3Ch, n = 9). EVs were enriched by differential centrifugation and characterized using nanoparticle tracking analysis, flow cytometry, and LCMS/MS proteomics. Associations between EV features and cognitive performance were explored, and cellular effects were assessed using a human astrocyte–endothelium co-culture model. EVs from non-MCI PSEN1E280A-APOE3 carriers displayed early molecular signatures related to vascular dysfunction and inflammation identified through direct comparison with MCI cases. These signatures were associated with poorer cognitive performance and induced detrimental effects in the GVU co-culture assay. In contrast, EVs from non-MCI PSEN1E280A-APOE3Ch carriers exhibited a distinct molecular profile, correlated with better cognitive outcomes, and preserved both astrocytic and endothelial integrity in vitro. These results suggest that EVs capture early pathophysiological changes in presymptomatic ADAD and reflect protective mechanisms in APOE3Ch carriers. EV profiling may therefore offer a valuable window into resistance in ADAD and a potential source of biomarkers for early detection and therapeutic monitoring.
Author: Pineda López, Lina Gisela
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7207463476