We genetically mapped a mutation in Add3 in FHH rats that decreases Add3 expression in various tissues, including brain and cerebral vessels, and further decreases with age in comparison with FHH.1 BN congenic rats in which Chr. 1 from BN rats containing 15 genes, including Add3, was transferred onto FHH genetic background. 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 well-defined feature 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 and IL-6 expression was markedly enhanced in comparison to scramble siRNA treated cells using a q-PCR array. Moreover, the expression of TGF-β2 and TGF-β3 was elevated by 2.0 ± 2.9 and 1.8 ± 1.8 folds, respectively, in Add3 DsiRNA treated astrocytes. In addition, the actin cytoskeleton was disrupted in Add3 DsiRNA treated astrocytes. We found that FHH rats exhibit a reduction in neuronal density and neuronal size in the hippocampus following the induction of hypertension with DOCA/salt. This was associated with loss of capillary density (22.7 ± 0.001% in FHH and 9.6 ± 0.014% in FHH.1 BN , 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 release of pro-inflammatory and fibrotic factors, which promotes inflammation and disrupts Aβ uptake, all of which may contribute to neurodegeneration and cognitive deficit associated with aging and hypertension in FHH rats.