Angiotensin receptor blockade does not modify tau pathology in line 66 tau-transgenic mice expressing the P301S mutation

The aggregation of the microtubule-associated protein tau is a hallmark in many neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Hypertension increases the risk of neurodegenerative diseases, and there is evidence that drugs targeting the renin-angiotensin system (RAS) to reduce blood pressure (BP) could potentially delay neurodegenerative disease onset due to their action on brain RAS. However, the effect of such treatment on pathologies associated with tau are understudied. We have treated three-month old line 66 (L66) tau-transgenic mice expressing the P301S mutation for six weeks with the angiotensin receptor blocker (ARB) candesartan at 5 mg/kg and investigated tau pathology, angiotensin II (Ang II) type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), neurones, microglia, and astrocytes using immunohistochemistry (IHC) and immunoblotting. AT1R and AT2R levels, as well as cortical thickness, number of neurones, GFAP-positive astrocytes and Iba1-positive microglia were all not affected by candesartan treatment. L66 mice had more human tau but less mouse pSer202 tau and total mouse tau, but candesartan treatment did not normalise these differences. Therefore, candesartan administered for six weeks at 5 mg/kg did not lead to a significant reduction of dementia-related pathologies in L66 tau-transgenic mice.