The Multifaceted Role of Extracellular Vesicles in Alzheimer's Disease

Abstract

Extracellular vesicles (EVs) are lipid bilayer nano- to micro-sized particles that carry biomolecules, such as proteins, lipids, and genetic material. Their composition depends on the cellular microenvironment and the health status of tissues. EVs are released by different cell types under distinct circumstances, mediating intercellular communication in both physiological and pathological contexts. In Alzheimer's disease (AD), EVs have been shown to influence pathological events, carrying neurotoxins, such as neuroinflammatory factors, pathogenic forms of amyloid-β, and phosphorylated tau into recipient neurons. This contributes to the propagation of AD pathology and exacerbates neuronal degeneration. However, under physiological conditions, EVs play key roles in maintaining tissue homeostasis. In the central nervous system (CNS), EVs derived from glial cells and neurons modulate synaptic plasticity and neuronal activity. Interestingly, EVs carrying neurotoxin molecules can cross the blood-brain barrier, making them attractive candidates as biomarkers for diagnosis with a minimally invasive approach to assess CNS alterations. Additionally, EVs contribute to the activation of neuroprotective pathways, participating in the periphery-to-brain signaling. Notably, alteration of EV content has been further proposed to have potential therapeutic applications. Herein, we summarize the multifaceted role of EVs in AD, emphasizing their role in promoting neuroprotection and exploring their contribution to our understanding of AD pathophysiology.

Keywords: Alzheimer's disease; biomarkers; extracellular vesicles; neuroinflammation; neuroprotection.

FIGURE 1

The multifaceted role of extracellular vesicles. Extracellular vesicles (EVs) perform multiple roles in the context of Alzheimer's disease. Under physiological conditions, glial and neuronal EVs contribute to synaptic support, neuroglial communication, attenuation of neuroinflammation, and protein transport. In their pathological role, EVs are implicated in the propagation of amyloid‐beta (Aβ) and tau proteins, synaptic dysfunction, neurodegeneration, and chronic inflammation. As biomarkers, EVs may carry microRNAs (miRNAs), Aβ, tau, cytokines, and other factors, offering valuable tools for the diagnosis and monitoring of disease progression. In the context of EV‐based therapies, approaches such as immunotherapy, anti‐inflammatory agents, gene editing, and the delivery of exercise‐induced factors have been proposed to enhance brain resilience and restore neuronal function. The figure was created with BioRender.com.