Down Regulation of Add3 in Astrocytes Disrupts the Actin Cytoskeleton in Association with Decreasing Small Molecule Uptake and May Contribute to Cognitive Deficits in FHH rats

Abstract

We previously reported that the expression of Add3 is decreased in various tissues, including brain and cerebral vessels, and further decreases with age in FHH rats. More recently, we demonstrated that Add3 dysfunction contributes to cerebral vascular impairments in FHH rats, and they exhibit BBB leakage and neurodegeneration after the development of hypertension. In addition, Aβ protein expression in the brain in FHH rats is increased as early as 8 weeks of age. Reactive astrogliosis is a common finding in neurodegenerative diseases and activated astrocytes promote neurodegeneration. Moreover, astrocyte dysfunction affects Aβ clearance and Aβ accumulation is a characteristic biomarker of Alzheimer's disease. To further explore whether astrocytes contribute to neurodegeneration and cognitive impairments in FHH rats, we knocked down Add3 expression using Add3 Dicer‐substrate RNAi (DsiRNA) in human astrocytes and found that GFAP expression was markedly enhanced in comparison to scrambled siRNA treated cells. F‐actin distribution was significantly reduced in the Add3 DsiRNA treated cells (19.3 ± 6.7%, n = 6) when compared to the control cells (34.9 ± 3.0%, n = 6). In addition, the Add3 DsiRNA treated cells took up less fluorescence‐labeled dextran (10 kD) than the control cells suggesting the capability of uptake of small molecule, such as Aβ may be diminished. We found that DOCA/salt induced hypertensive FHH rats exhibit a reduction in neuronal density and size in the hippocampus. This was associated with loss of capillary density (22.7 ± 0.001% in FHH and 9.6 ± 0.014% in control rats, n = 7 and 9, respectively), and greater expression of GFAP positive astrocytes and loss of neurons in affected areas. Hypertensive FHH rats took 2.5 times longer to escape from an eight‐arm water maze as compared to control strains. These results suggest that down regulation of Add3 in astrocytes disrupts the actin cytoskeleton to induce reactive astrogliosis and may affect Aβ clearance, all of which may contribute to neurodegeneration and cognitive deficit associated with aging and hypertension in FHH rats.Support or Funding InformationThis study was supported by grants HL36279 (RJR) and DK104184 (RJR), AG050049 (FF), P20GM104357 (RJR, FF ) from the National Institutes of Health; 16GRNT31200036 (FF) from the American Heart Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.