Amyloid-β (Aβ) accumulation in the hippocampus is an essential event in the pathogenesis of Alzheimer's disease. Insoluble Aβ is formed through the sequential proteolytic hydrolysis of the Aβ precursor protein, which is cleaved by proteolytic secretases. However, the pathophysiological mechanisms of Aβ accumulation remain elusive. Here, we report that rats fed high-phytate diets showed Aβ accumulation and increased apoptotic neuronal cell death in the hippocampus through the activation of the amyloidogenic pathway in the hippocampus. Immunoblotting and immunohistochemical analyses confirmed that the overexpression of BACE1 β-secretase, a critical enzyme for Aβ generation, exacerbated the hippocampal Aβ accumulation in rats fed high-phytate diets. Moreover, we identified that parathyroid hormone, a physiological hormone responding to the phytate-mediated dysregulation of calcium and phosphate homeostasis, plays an essential role in the transcriptional activation of the Aβ precursor protein and BACE1 through the vitamin D receptor and retinoid X receptor axis. Thus, our findings suggest that phytate-mediated dysregulation of calcium and phosphate is a substantial risk factor for elevated Aβ accumulation and apoptotic neuronal cell death in rats.
Keywords: APP; APP processing; Ca2+ and Pi dyshomeostasis; amyloid-β; high-phytate diet; retinoid X receptor; β-secretases (Bace1).