The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

Abstract

BackgroundThe pathological features of the common neurodegenerative conditions, Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.ResultsProtein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels.ConclusionOur results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.

Role of extracellular Hydrogen peroxide in regulation of iron homeostasis genes in neuronal cells: Implication in iron accumulation

“…We speculate that oxidative stress induced decrease in native APP as the cause for Fpn degradation. Our study also support the recent findings of reduced Fpn level in brain in Alzheimer's disease [40] in which native APP level is reduced with simultaneous generation of increased oxidative stress due to Abeta formation [5].…”

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

“…This hypothesis is further supported by the previous findings of significant reduction of Fpn levels in hippocampal lysates from AD brains, which corroborate the impairment of Fe export also in the brain [58].…”

The Retromer Complex protein VPS35 Modulates Iron Homeostasis by Regulating Hepcidin-induced Ferroportin Degradation

“…In both diseases, iron accumulation has been implicated in the pathology and pathogenesis (Good, 1992;Martin, 2008;Ayton, 2015). Interestingly, dysregulation of Hepcidin has also been observed in Parkinson patients (Raha, 2013). VPS35 involvement in iron regulation inferred from this study is consistent with the reported disease relevance of VPS35 and iron elevation implicated in the pathogenesis of the two progressive neurodegenerative diseases.…”