Abstract
Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.
Highlights
We observed an age-dependent downregulation of Fpn at the protein level in the hippocampus and frontal cortex of APPswe/PS1dE9 (APP/PS1) mice compared with wild-type littermates (Fig. 1A, B and Supplementary Fig. S1A)
Excess deregulated brain iron has been widely reported in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD) [45], Huntington’s disease [46], amyotrophic lateral sclerosis (ALS) [47], and Alzheimer’s disease (AD) [1, 48]
We demonstrated that Fpn, the only known iron exporter, was downregulated with age in an AD mouse model and AD patients, consistent with multiple previous reports [25, 49, 50]
Summary
Considering the excess iron accumulation in AD, which induces significantly higher ROS production in the brain, ferroptosis is likely involved in the neuronal loss and cognitive impairment of AD. In the central nervous system, Fpn is distributed in most cell types, including neurons, astrocytes, oligodendrocytes, and brain microvascular endothelial cells [21]. It is essential for mouse embryonic development, forebrain patterning and neural tube closure [22]. We reported that the expression of Fpn is decreased in the brains of an AD mouse model and AD patients, in which abnormal iron deposition has been observed.
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