Extracellular Vesicles From 3xTg-AD Mouse and Alzheimer's Disease Patient Astrocytes Impair Neuroglial and Vascular Components

Luis Alfonso González-Molina; Juan Villar-Vesga; Julián Henao-Restrepo; Andrés Villegas; Francisco Lopera; Gloria Patricia Cardona-Gómez; Rafael Posada-Duque

doi:10.3389/fnagi.2021.593927

Extracellular Vesicles From 3xTg-AD Mouse and Alzheimer's Disease Patient Astrocytes Impair Neuroglial and Vascular Components

Front Aging Neurosci. 2021 Feb 19:13:593927. doi: 10.3389/fnagi.2021.593927. eCollection 2021.

Authors

Luis Alfonso González-Molina^{1

2}, Juan Villar-Vesga^{1

2}, Julián Henao-Restrepo^{1

2}, Andrés Villegas³, Francisco Lopera³, Gloria Patricia Cardona-Gómez¹, Rafael Posada-Duque^{1

2}

Affiliations

¹ Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellin, Colombia.
² Facultad de Ciencias Exactas y Naturales, Instituto de Biología, Universidad de Antioquia, Medellin, Colombia.
³ Neurobank, Neuroscience Group of Antioquia, Faculty of Medicine, SIU, University of Antioquia, Medellin, Colombia.

Abstract

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.

Keywords: 3xTg-AD mice; astrocytes; endothelial disruption; extracellular vesicles; familiar Alzheimer’s disease; human astrocytes; sporadic Alzheimer disease.