Extracellular Vesicles and Purinergic Signaling in Alzheimer's Disease-Joining Forces for Novel Therapeutic Approach

Abstract

Neurodegenerative diseases, including Alzheimer's disease (AD), are a global problem affecting millions of people. Thanks to years of research and huge efforts, it has been possible to discover the pathophysiological changes accompanying Alzheimer's disease at the cellular level. It turns out that the formation of amyloid-beta plaques and hyperphosphorylation of tau protein in the brain play a key role in disease development. Purinergic signaling (PS) is implicated in the pathophysiology of several disorders in the central nervous system, and recent findings link some disturbances in PS with Alzheimer's disease. The primary objective of our review is to comprehensively explore and identify key purinergic signaling targets that hold therapeutic potential in the treatment of patients suffering from the disease. In particular, we focus on the dual role of purinergic compounds and extracellular vesicles (EVs), which have emerged as critical components in cellular communication and disease modulation. The extracellular vesicles that are naturally released by various cells fulfill the role of communication tools, also by harnessing the purinergic compounds. In this context, our review presents a thorough and integrative analysis of how extracellular vesicles can influence purinergic signaling and how this interaction might be leveraged to develop novel, targeted treatment strategies. Ultimately, this line of research may lead to innovative therapeutic approaches that are not only effective in slowing or halting disease progression but also demonstrate a high degree of biocompatibility and safety for the human organism.

Keywords: P2X receptors; extracellular vesicles; neurodegenerative diseases; neuroinflammation; purinergic signaling.

Figure 1

Development of neuroinflammation in AD. Amyloid-beta monomers are formed as a result of the transmembrane APP cleavage by secretases. Monomers group into more complex structures, which are oligomers, fibrils, and plaques. Formation of plaques results in the initiation of an inflammatory response, which initiates hyperphosphorylation of tau protein. Tau protein is detached from microtubules, and neurofibrillary tangles are formed, which have a toxic effect on the nervous cells. Healthy neurons become diseased and finally undergo degradation, which is another important factor initiating inflammation in the central nervous system. Created in BioRender: Lewandowska, J. (2025), https://BioRender.com/edmwusi, based on [9,28].

Figure 2

Changes in the purinergic system in Alzheimer’s disease. During the course of Alzheimer’s disease, the release of ATP outside the cells via lytic and nonlytic mechanisms occurs in the central nervous system. Activation of P2X7 receptor enhances inflammatory processes. The enzyme TNAP (tissue nonspecific alkaline phosphatase), involved in the degradation of ATP to adenosine, may also contribute to neurotoxicity by dephosphorylating tau protein. In turn, ecto-5′-nucleotidase (CD73) is responsible for the conversion of AMP to adenosine. Ado production leads to activation of A₂A receptors, the excessive stimulation of which intensifies neurodegenerative processes. Created in BioRender. Lewandowska, J. (2025), https://biorender.com/0ci7425.

Figure 3

Formation and classification of extracellular vesicles (EVs). Vesicles are secreted by all cells of the human body and found in all tissues and body fluids. EVs are divided into two main types depending on their size and mechanism of formation: microvesicles and exosomes, both released into the intercellular space. Created in BioRender. Lewandowska, J. (2025), https://biorender.com/fpkc2br.

Figure 4

Schematic composition of extracellular vesicles (EVs) released from cells such as mesenchymal stem cells (MSCs) by exocytosis. Created in BioRender. Lewandowska, J. (2025), https://BioRender.com/kcz73yw, based on [160].

Figure 5

The complex picture of interactions within the diseased central nervous system. Microglia, extracellular vesicles secreted by, among others, mesenchymal stem cells, as well as cytokines and purine compounds, have the ability to modulate the functioning of CNS cells. Depending on the content of the vesicles, this action can have a neurodegenerative or neuroprotective effect on neurons. Further details are provided in the main text. Created in BioRender. Lewandowska, J. (2025), https://BioRender.com/q56o75m, based on [159,160].