Amyloid β and Extracellular Vesicles in Alzheimer’s Disease

Doctoral thesis, 2026

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that is characterized by progressive neuronal loss and associated cognitive decline. Protein aggregation and extracellular deposition of amyloid-β (Aβ) fibrils is a central pathological hallmark of AD, but, prior to Aβ plaque deposition, Aβ can also accumulate intracellularly. This has been linked to endolysosomal dysfunction. Although Aβ as a driver of AD pathology is well established, the exact events that initiate Aβ pathology and drive disease progression remain unclear. This makes the development of effective disease-modifying treatments a major unresolved challenge. Better understanding of the cellular and molecular mechanisms that underlie Aβ pathology is therefore needed.

This thesis aims to clarify the role of extracellular vesicles (EVs) in Aβ aggregation and accumulation, focusing on the disease-associated Aβ(1-42) variant. EVs are cell-secreted vesicles that have been implicated in cell-cell propagation of Aβ and as potential modulators of Aβ plaque formation and toxicity. My work shows that EVs, independent of their cell-origin, delay in vitro Aβ(1-42) aggregation by interfering with the fibril elongation step. This drives the formation of short fibrils that could be neurotoxic. To better understand EV-mediated aggregation inhibition, I examined how surface-associated proteins, carbohydrates and lipids contribute. I found that removal of EV surface proteins and, albeit to a considerably lesser extent, carbohydrates, enhances the aggregation inhibitory effect. This suggests that the EV limiting membrane is a significant modulator of Aβ(1–42) aggregation but that its effect can be masked or counteracted by other EV surface biomolecules. This notion was supported by a study on synthetic lipid vesicles which, furthermore, pointed out the importance of lipid raft-like microdomains and ganglioside clustering. Finally, I report on a bidirectional crosstalk between endolysosomal Aβ(1–42) and EVs whereby Aβ(1–42) accumulation alters the EV proteome and enhances EV release in a way that potentiates the aggregation effect and, in turn, further enhances Aβ(1–42) intraneuronal accumulation.

Altogether, this thesis contributes new insights into how EVs modulate Aβ(1–42) self-assembly and accumulation in Alzheimer’s disease. This work is important for understanding the basic mechanisms that drive Aβ pathology, and, ultimately, for development of effective therapeutics.