# Effect of ferric citrate on hippocampal iron accumulation and widespread molecular alterations associated with cognitive disorder in an ovariectomized mice model

## TL;DR

This study shows that iron accumulation in ovariectomized mice leads to cognitive and motor impairments, possibly through changes in hippocampal proteins and iron metabolism.

## Contribution

The study introduces a novel mouse model linking iron accumulation and cognitive decline in postmenopausal women.

## Key findings

- Iron exposure caused histopathological changes in the hippocampus of ovariectomized mice.
- Iron accumulation altered hippocampal proteomics, including increased TFR1 and DMT1 protein expression.
- Cognitive and motor functions declined in mice with iron accumulation and ovariectomy.

## Abstract

Nowadays, the prevalence of cognitive impairment in women has gradually increased, especially in postmenopausal women. There were few studies on the mechanistic effects of iron exposure on neurotoxicity in postmenopausal women. The aim of this study is to investigate the effect of iron accumulation on cognitive ability in ovariectomized mice and its possible mechanism and to provide a scientific basis for the prevention of cognitive dysfunction in postmenopausal women.

Female C57BL/6N ovariectomized model mice were induced with ferric citrate (FAC). The mice were randomly divided into 5 groups: control, sham, ovariectomized (Ovx), Ovx + 50 mg/kg FAC (Ovx + l), and Ovx + 100 mg/kg FAC (Ovx + h). The impact of motor and cognitive function was verified by a series of behavioral tests. The levels of serum iron parameters, malondialdehyde, and superoxide dismutase were measured. The ultrastructure of mice hippocampal microglia was imaged by transmission electron microscopy. The differential expression of hippocampal proteins was analyzed by Tandem Mass Tag labeling.

Movement and cognitive function in Ovx + l/Ovx + h mice were significantly decreased compared to control and Sham mice. Then, iron exposure caused histopathological changes in the hippocampus of mice. In addition, proteomic analysis revealed that 29/27/41 proteins were differentially expressed in the hippocampus when compared by Ovx vs. Sham, Ovx + l vs. Ovx, as well as Ovx + h vs. Ovx + l groups, respectively. Moreover, transferrin receptor protein (TFR1) and divalent metal transporter 1 (DMT1) protein expression were significantly increased in the iron accumulation mice model with ovariectomy.

Iron exposure could cause histopathological damage in the hippocampus of ovariectomised mice and, by altering hippocampal proteomics, particularly the expression of hippocampal iron metabolism‐related proteins, could further influence cognitive impairment in ovariectomized mice.

Iron accumulation mice model with ovariectomy could lead to the decline of movement and cognitive function. Iron accumulation could cause histopathological damage in the hippocampus of ovariectomized mice and, by disturbing hippocampus proteome, particularly the expression of hippocampal iron metabolism‐related proteins, could further influence cognitive impairment in ovariectomized mice.