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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.

SUBMITTER: Villar-Vesga J

PROVIDER: S-EPMC7705379 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Villar-Vesga Juan J Henao-Restrepo Julián J Voshart Daniëlle C DC Aguillon David D Villegas Andrés A Castaño Diana D Arias-Londoño Julián D JD Zuhorn Inge S IS Ribovski Laís L Barazzuol Lara L Cardona-Gómez Gloria P GP Posada-Duque Rafael R

Frontiers in aging neuroscience 20201111

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 endothel ...[more]

PMID: 33281599

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Project description:Astrocytes are specialized glial cells that are essential components of the neurovascular unit (NVU) and are involved in neurodevelopment, brain maintenance and repair, and neurodegeneration. Astrocytes mediate these processes by releasing cellular mediators such as extracellular vesicles (EVs). EVs are vehicles of cell-cell communication and have been proposed as mediators of damage in AD. However, the transcellular mechanism by which Alzheimer disease (AD) astrocytes impair the function of NVU components is poorly understood. Therefore, we evaluated the effects of adult PS1-KI and 3xTg-AD astrocyte conditioned media (CM) and EVs on NVU components (neuroglia and endothelium) in vitro. Additionally, SAD and FAD astrocyte-derived EVs (A-EVs) were characterized, and we evaluated their effects on NVU in cocultured cells in vitro and on intrahippocampal CA1 cells in vivo. Surprisingly, cultured 3xTg-AD astrocytes showed increased glial fibrillary acidic protein (GFAP) reactivity compared to PS1-KI astrocytes, which denotes astrocytic hyperreactivity. CM from adult mice 3xTg-AD astrocytes increased cell-cell gaps between endothelial cells, filopodia-like dendritic protrusions in neurons and neuronal and endothelial cell death. 3xTg-AD A-EVs induced neurotoxicity and increased astrocyte GFAP reactivity. Cultured human postmortem astrocytes from AD patients also increased GFAP reactivity and EVs release. No differences in the size or number of A-EVs were detected between AD and control samples; however, both SAD and FAD A-EVs showed increased expression of the surface marker aquaporin 4. A-EVs induced cytotoxicity and astrocyte hyperactivation: specifically, FAD A-EVs induced neuroglial cytotoxicity and increased gaps between the endothelium, while SAD A-EVs mainly altered the endothelium. Similarly, both AD A-EVs increased astrocyte GS reactivity and vascular deterioration in vivo. We associated this finding with perivascular reactive astrocytes and vascular deterioration in the human AD brain. In summary, these results suggest that AD A-EVs impair neuroglial and vascular components.

Project description:Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-? precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-?(1-40), phospho-tau(Thr?231) and active glycogen synthase kinase-3? (aGSK-3?). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with ?-secretase inhibitors, but not ?-secretase inhibitors, caused significant reductions in phospho-Tau(Thr?231) and aGSK-3? levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-?, in GSK-3? activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.

Dataset Information

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

Publications

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

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