Iron uptake in quiescent and inflammation-activated astrocytes: A potentially neuroprotective control of iron burden

Abstract

Astrocytes play a crucial role in proper iron handling within the central nervous system. This competence can be fundamental, particularly during neuroinflammation, and neurodegenerative processes, where an increase in iron content can favor oxidative stress, thereby worsening disease progression. Under these pathological conditions, astrocytes undergo a process of activation that confers them either a beneficial or a detrimental role on neuronal survival. Our work investigates the mechanisms of iron entry in cultures of quiescent and activated hippocampal astrocytes. Our data confirm that the main source of iron is the non-transferrin-bound iron (NTBI) and show the involvement of two different routes for its entry: the resident transient receptor potential (TRP) channels in quiescent astrocytes and the de novo expressed divalent metal transporter 1 (DMT1) in activated astrocytes, which accounts for a potentiation of iron entry. Overall, our data suggest that at rest, but even more after activation, astrocytes have the potential to buffer the excess of iron, thereby protecting neurons from iron overload. These findings further extend our understanding of the protective role of astrocytes under the conditions of iron-mediated oxidative stress observed in several neurodegenerative conditions.

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

“…Astrocytes are considered important regulators of iron homeostasis that become activated under pathological conditions, exerting either beneficial or detrimental effects on the surrounding environment (Tulpule et al, 2010;Pelizzoni et al, 2013). Since Fxn is known to be directly implicated in mitochondrial iron-sulfur cluster biogenesis, the increase in superoxide production and the alterations to mitochondrial morphology after Fxn depletion in astrocytes supports the idea that increasing mitochondrial iron content favors oxidative stress within astroglial cells.…”

The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin

“…This process leads to neuronal iron overloading and toxicity 173,174 . The same channels facilitate iron protection or iron burden depending on the cell type and iron overloading status 174,175 .…”

“…The small interstitial space separating the glia limitans and endothelial cells must be traversed to allow penetration into the brain. Under healthy conditions, astrocytes acquire iron across the interstitial space using distinct NTBI mechanisms such as citrate, ATP, ascorbic acid, DMT1, and Zip 177,178 (Fig. 4a).…”

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

“…There is undoubtedly localized communication between the BMVEC and their spatially adjacent astrocytes [8, 14], and astrocytes in direct contact with both BMVEC and neurons are uniquely positioned to influence neuronal energy metabolism [168] and synaptic function [169]. Furthermore, recent evidence suggests that astrocytes act as a buffer of excess iron, preventing over accumulation by neighboring neurons [170]. We introduce the following model regarding iron regulation throughout the neurovascular unit of the adult mammal.…”