Seminar

Role of peripheral exosomes in the pathophysiology of Alzheimer’s disease

Charles Ramassamy

Alzheimer’s disease (AD) stands as an escalating public health crisis, affecting over 55 million individuals globally, with projections indicating a prevalence of 139 million by 2050 (World Alzheimer Report, 2022). The neuropathological landscape of AD is characterized by misfolded proteins, namely amyloid-ß peptide (Aß) and phosphorylated tau, driving neuroinflammation, oxidative stress, synaptic loss, and neuronal death. Interestingly, several metabolic disorders (diabetes, cardio-vascular diseases, obesity, dyslipidemia, dysbiosis of the gut microbiota..) are known to increase the risk of developing AD, unveiling a profound interplay between peripheral health and brain neuropathology. Such metabolic disorders are associated with peripheral inflammation and oxidative stress, fostering a chronic low-grade pro-inflammatory state known as inflamm’aging, initiated decades before AD diagnosis. Although most studies are broadly consistent in that peripheral inflammation may exacerbate cognitive decline, the mechanistic link between certain inflammatory mediators and neurodegeneration remains elusive, given their limited ability to cross the blood-brain barrier (BBB). Extracellular vesicles (EVs) are a variety of nanoscale membrane vesicles released by almost all cell types and are emerging as pivotal players in neurodegenerative disorders like AD. EVs can participate in Aβ production and oligomerization, disseminate Aβ, phospho-tau, or alpha-synuclein to neighboring neurons, and act as "seeds" to amplify the toxic effects of misfolded proteins. Our hypothesis posits peripheral EVs as potential mediators bridging peripheral disturbances and the brain, leading to AD. Although cumulative studies have demonstrated the permeability of peripheral EVs through the BBB, this question remains unclear because it depends on different parameters, such as their specific molecular cargo and surface decoration, which can modify their physicochemical properties. We have investigated whether peripheral EVs from young, healthy donors, AD patients, and age-matched healthy control patients cross differently the endothelial cells bEnd.3 and their internalization by neuronal and microglial cells in a Transwell® model. We have then further scrutinized peripheral EVs' influence on microglial activity following the bEnd.3 permeability. The passage of peripheral EVs through the BBB and their uptake by neuronal and glial cells was also investigated in vivo following their microinjection into the blood circulation of 2-days post-fertilization of different transgenic zebrafish Danio rerio. Considering the therapeutic challenges posed by BBB impermeability, we have also explored another application of EVs, their potential as innovative drug delivery vehicles for AD treatment. Specifically, we compared the toxicity and efficacy of donepezil-loaded EVs against polymeric nanoparticles (NPs) in vitro and in vivo models. In the presentation, I will delineate our recent findings, underscoring the pivotal role of peripheral EVs from healthy and AD patients, their communication to the brain, and their therapeutic potential as brain-targeted drug delivery systems.