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.
Highlights
The neurovascular unit (NVU) is a functional structure composed of the endothelial microvasculature that makes up the blood brain barrier (BBB), neurons, astrocytes, pericytes, microglia and the basal lamina (Hawkins and Davis, 2005; Muoio et al, 2014)
Endothelial cells treated with knock-in mouse for presenilin 1 (PS1-KI) astrocyte conditioned media (CM) showed an increase in condensed nuclei; this effect was stronger in cells treated with triple transgenic Alzheimer’s disease mouse (3xTg-Alzheimer disease (AD)) astrocyte CM (Figures 1G,H)
We quantified the number and area of gaps formed between endothelial cells treated with astrocyte CM (Figure 1I) and found that adult 3xTg-AD astrocyte CM treatment induced increased numbers and areas of gaps between endothelial cells compared with the control conditions (Figure 1I)
Summary
The neurovascular unit (NVU) is a functional structure composed of the endothelial microvasculature that makes up the blood brain barrier (BBB), neurons, astrocytes, pericytes, microglia and the basal lamina (Hawkins and Davis, 2005; Muoio et al, 2014). Astrocytes are crucial for neurodevelopment and the maintenance and repair of the cellular microenvironment in the NVU (Rothstein et al, 1996; Aubert et al, 2007; Attwell et al, 2010; Mishra et al, 2016; Boulay et al, 2017; Tapella et al, 2018). Astrocytes release a broad variety of cellular mediators, such as cytokines, growth factors, neurotransmitters, and extracellular vesicles (EVs) (Farina et al, 2007; Schitine et al, 2015; Verkhratsky et al, 2016)
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