Lower Expression of Ndfip1 Is Associated With Alzheimer Disease Pathogenesis Through Decreasing DMT1 Degradation and Increasing Iron Influx

Abstract

We have previously reported that high expression of divalent metal transporter 1 (DMT1) plays a crucial role in iron dyshomeostasis and β-amyloid (Aβ) peptide generation in the brain of Alzheimer’s disease (AD). Recent studies have shown that Nedd4 family interacting protein 1 (Ndfip1) can degrade DMT1 through ubiquitination pathway and reduce the accumulation of intracellular iron. The present study aims to evaluate whether Ndfip1 is involved in AD pathogenesis through mediating DMT1 degradation and iron metabolism. β-amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mouse and Ndfip1 transfected SH-SY5Y cells were used in this study. Immunohistochemistry and Western blot were performed to examine the distribution and expression levels of Ndfip1 and DMT1. In addition, ELISA and calcein fluorescence were carried out for analyzing the levels of Aβ peptide and iron influx, respectively. The results showed that Ndfip1 immunoreactivity was decreased in the cortex and hippocampus of APP/PS1 mice, compared with wild type (WT) controls. Colocalization of Ndfip1 and Aβ within senile plaques could be observed. Immunoblot analyses showed that low expression of Ndfip1 and high expression of DMT1 proteins were detected in APP/PS1 mouse brain, compared with age-matched WT animals. Overexpression of Ndfip1 down-regulated DMT1 expression, and reduced iron influx and Aβ secretion in SH-SY5Y cells. Further, overexpressed Ndfip1 significantly attenuated iron-induced cell damage in Ndfip1 transfected cells. The present study suggests that lower expression of Ndfip1 might be associated with the pathogenesis of AD, through decreasing DMT1 degradation and increasing iron accumulation in the brain.

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

“…FPN1, on the other hand, plays an essential role in the export of iron from cells to the blood [66] . Interestingly, in vitro studies have demonstrated that silencing of endogenous DMT1 not only reduces iron influx but also leads to reductions in APP expression and Aβ production [67][68][69] . Pharmacological inhibition of DMT1 also seems to reduce iron-induced tau pathology in human neuroblastoma SH-SY5Y cells, through the inhibition of the tau kinases CDK5 and GSK-3β [70] .…”

DMT1 Expression and Iron Levels at the Crossroads Between Aging and Neurodegeneration

“…In addition, signaling derangement with DMT1 misregulation was also presents in Alzheimer models. In fact, the decrease of Ndfip1 in the cortex and hippocampus of APP SWE /PS1 ΔE9 transgenic mice was associated with the up-regulation of both (–) and (+) IRE DMT1 isoforms (Tian et al, 2018). Tian et al (2018) also showed how the down-regulation of DMT1, with reduced iron uptake and decreased Aβ(1–42) peptide secretion, occurs after transient overexpression of Ndfip1 in SH-SY5Y human neuroblastoma cells stably over-expressing APP sw .…”

“…In fact, the decrease of Ndfip1 in the cortex and hippocampus of APP SWE /PS1 ΔE9 transgenic mice was associated with the up-regulation of both (–) and (+) IRE DMT1 isoforms (Tian et al, 2018). Tian et al (2018) also showed how the down-regulation of DMT1, with reduced iron uptake and decreased Aβ(1–42) peptide secretion, occurs after transient overexpression of Ndfip1 in SH-SY5Y human neuroblastoma cells stably over-expressing APP sw . Accordingly, in immortalized microglia cells, the Aβ (1–42) treatment induced pan-DMT1 up-regulation (McCarthy et al, 2018).…”

“…Furthermore, several reports have recently highlighted that, during aging, iron and DMT1 accumulate in the frontal cortex of the APP SWE /PS1 ΔE9 transgenic mouse model (Xian-hui et al, 2015), where both (–)/(+) IRE DMT1 were also increased in the cortex and hippocampus compared with wild type-control (Zheng et al, 2009), potentially contributing to increasing to the risk of developing AD. Interestingly, (–)/(+) IRE DMT1 up-regulation in the cortex and hippocampus of the APP SWE /PS1 ΔE9 transgenic mouse model was recently shown as a consequence of down-regulation of Ndfip1, the NEDD4 family interacting protein 1 (Tian et al, 2018), which modulates DMT1 degradation through ubiquitination pathway (Foot et al, 2011). Again, (–)IRE DMT1 up-regulation was associated with a quantitative, age-dependent increase of heavy metals in the frontal cortex of a ”natural” rodent model of AD, named Octodon degus (Braidy et al, 2017), with impaired lysosomal function.…”

Identification and Functional Verification of MicroRNA-16 Family Targeting Intestinal Divalent Metal Transporter 1 (DMT1) in vitro and in vivo

“…Abnormal expression of DMT1 is harmful to health. It is proposed that DMT1 mutant rodents exhibit microcytic, hypochromic anemia (Fleming et al, 1998; Canonne-Hergaux et al, 2000), whereas high-level expression of DMT1 contributes to neurodegenerative diseases (Salazar et al, 2008; Tian et al, 2018). A tight regulation of DMT1 expression is indispensable for maintenance of life in eukaryotes.…”