High-Phytate Diets Increase Amyloid β Deposition and Apoptotic Neuronal Cell Death in a Rat Model.

Hyo-Jung Kim,Yun-Shin Jung,Ok-Hee Kim,Yun-Jae Jung,Byung-Chul Oh

doi:10.3390/nu13124370

Abstract

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.

Highlights

Amyloid β is derived from the proteolytic cleavage of the amyloid precursor protein (APP) by APP processing enzymes [1,2], including β-secretase (BACE1) and γ-secretase (PSEN1), thereby generating either Aβ40 or Aβ42 insoluble peptide [2,3]
We previously reported that a high-phytate, low-calcium diet is a crucial risk factor for phosphate overloading and renal phosphate wasting associated with crystal nephropathy, renal fibrosis, bone loss, and secondary hyperparathyroidism [11]
We found that rats fed high-phytate diets showed greater Aβ accumulation and an elevated rate of apoptotic neuronal cell death in the hippocampus

Summary

Introduction

Amyloid β is derived from the proteolytic cleavage of the amyloid precursor protein (APP) by APP processing enzymes [1,2], including β-secretase (BACE1) and γ-secretase (PSEN1), thereby generating either Aβ40 or Aβ42 insoluble peptide [2,3]. The accumulation of insoluble Aβ has been suggested to damage structural and functional brain networks, resulting in cognitive impairment [4]. In late-onset sporadic AD, the accumulation of Aβ in the brain has been attributed to defective Aβ clearance [6], as well as elevated expression and increased enzymatic activity of BACE1 [6]. Dietary phytate is the major form of dietary phosphorus in cereals and legumes, accounting for as much as 80% of total phosphate [7,8]. We previously showed that phytate dysregulates the homeostasis of both Ca2+ and phosphate by decreasing Ca2+

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