Differential Profile of Systemic Extracellular Vesicles From Sporadic and Familial Alzheimer’s Disease Leads to Neuroglial and Endothelial Cell Degeneration

Abstract

Evidence suggests that extracellular vesicles (EVs) act as mediators and biomarkers of neurodegenerative diseases. Two distinct forms of Alzheimer disease (AD) are known: a late-onset sporadic form (SAD) and an early-onset familial form (FAD). Recently, neurovascular dysfunction and altered systemic immunological components have been linked to AD neurodegeneration. Therefore, we characterized systemic-EVs from postmortem SAD and FAD patients and evaluated their effects on neuroglial and endothelial cells. We found increase CLN-5 spots with vesicular morphology in the abluminal portion of vessels from SAD patients. Both forms of AD were associated with larger and more numerous systemic EVs. Specifically, SAD patients showed an increase in endothelial- and leukocyte-derived EVs containing mitochondria; in contrast, FAD patients showed an increase in platelet-derived EVs. We detected a differential protein composition for SAD- and FAD-EVs associated with the coagulation cascade, inflammation, and lipid-carbohydrate metabolism. Using mono- and cocultures (endothelium-astrocytes-neurons) and human cortical organoids, we showed that AD-EVs induced cytotoxicity. Both forms of AD featured decreased neuronal branches area and astrocytic hyperreactivity, but SAD-EVs led to greater endothelial detrimental effects than FAD-EVs. In addition, FAD- and SAD-EVs affected calcium dynamics in a cortical organoid model. Our findings indicate that the phenotype of systemic AD-EVs is differentially defined by the etiopathology of the disease (SAD or FAD), which results in a differential alteration of the NVU cells implied in neurodegeneration.

Beta-Secretase 1 Underlies Reactive Astrocytes and Endothelial Disruption in Neurodegeneration

“…Although we did not observe changes between dementia cases by immunoprecipitation, it was clear by confocal microscopy that BACE1 was overregulated mainly in astrocytes on FAD and SAD groups, with a particular association with vessels in SAD. Additionally accumulated CLDN5 was found according to previous reports (Villar-Vesga et al, 2020;González-Molina et al, 2021). Such BACE1 + reactive astrocytes associated to disrupted vessels were also closer but not overlapping with PHF-tau.…”

“…Complementarily to these data, we have found differential patterns of astrocytes implication in dementia using additional markers such as AQP4, GS1, GLAST1, and for ECs such as Lectin UEA, vimentin, PECAM1 and CLDN5. However, SAD always showed more affection in relationship with disrupted vessels, less thickness, and more production of CLDN5 + extracellular vesicles (EVs) [Henao-Restrepo J et al data non published ( Villar-Vesga et al, 2020 ; González-Molina et al, 2021 )]. Furthermore, the study from Gonzalez-Molina et al suggested that EVs from astrocytes of 3xTgAD mice and AD human brain carried out messages that produced endothelial disruption and neuronal retraction ( González-Molina et al, 2021 ).…”

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

“…Figure 1 shows the difference between young or normal BBB and aged or dysfunctional BBB. (Bell and Zlokovic, 2009;Grinberg and Thal, 2010;Richardson et al, 2012;Rouhl et al, 2012;Sagare et al, 2012) Yes (Salmina et al, 2010;Villar-Vesga et al, 2020;Chacón-Quintero et al, 2021;González-Molina et al, 2021) Yes (Wardlaw et al, 2003;Zhang et al, 2014;Rajani et al, 2018;Wang et al, 2018;Tayler et al, 2021;Zhu et al, 2021) Extracellular components…”

Engineering extracellular vesicles for Alzheimer's disease: An emerging cell‐free approach for earlier diagnosis and treatment

“…treatment to halt the progression of AD and no systemic biomarkers for early diagnosis of AD (Villar-Vesga et al, 2020). Early detection and intervention of AD is key in prevention, lowering the economic burden, and improving patient quality of life.…”