Abstract 35: Gamma Adducin Dysfunction Leads To Cerebrovascular Distention, Blood Brain Barrier Leakage, And Cognitive Deficits In The Fawn-hooded Hypertensive Rats

We have previously identified an inactivating mutation of ADD3 in FHH rats which is associated with impaired myogenic reactivity of renal arterioles and podocyte function, and contributes to the development of CKD. We have found that SNPs in human ADD1 or ADD3 in the same region as Add3 in FHH rats are linked to reductions in brain volumes and impaired performance on cognitive tests in 4,286 elderly patients (67-90 years old) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), but the mechanisms of these pathologies are unclear. The present study examined cerebral hemodynamics and cognitive function in FHH versus FHH.1BN and FHH. Add3 rats that express the WT Add3 gene. The myogenic responses of the middle cerebral artery (MCA) and parenchymal arterioles (PA) were impaired in FHH rats. MCA diameter decreased by 15-20% in FHH.1BN (n = 27) and FHH. Add3 (n = 10) transgenic rats, but increased by 9 ± 3% in FHH rats (n = 15) when perfusion pressure was increased from 40 to 160 mmHg. PA diameter increased by 3.16 ± 2.79% in FHH (n = 5) rats versus a 19 ± 3% and 13 ± 2% decrease FHH. Add3 (n = 4) and FHH.1BN (n = 6), respectively, when pressure was increased from 10 to 40 mmHg. Autoregulation of surface and deep cortical blood flow was impaired in FHH rats and rose by 48 ± 3% (n = 22) and 41 ± 3% (n = 12), respectively, versus 32 ± 3% (n = 7) and 16 ± 5% (n = 6) in FHH. Add3 rats when MAP was increased from 100 to 160 mmHg. By using a fluorescent microscope to examine 60 μm brain sections, it was revealed that the outer diameters of PAs were distended in FHH in comparison to FHH.1BN and FHH. Add3 transgenic rats when systemic pressure was increased to 160 mmHg. Blood brain barrier leakage was also greater in FHH rats than in FHH.1BN and FHH. Add3 rats after acute elevations in pressure. FHH (n=16) rats took 40- 50% longer to navigate an eight-arm water maze than FHH. Add3 (n=11) and FHH.1BN (n=7) rats. These results indicate that variants that alter Add3 function promote cognitive dysfunction in FHH rats by altering cerebral hemodynamics and may play a similar role in cognitive deficits in elderly patients in the ARIC-NCS study. This study suggests that blood pressure should be strictly controlled in hypertensive patients identified with ADD3 variants to prevent dementia.