The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice

Abstract

Ceruloplasmin (CP) plays an important role in maintaining iron homeostasis. Cp gene knockout (Cp-/-) mice develop a neurodegenerative disease with aging and show iron accumulation in the brain. However, iron deficiency has also been observed in 3 M Cp-/- mice. The use of systemic Cp gene knockout is insufficient to reveal specific functions for CP in the central nervous system. Considering recent discoveries that astrocytes synthetize the majority of brain CP, we generated astrocyte conditional Cp knockout (CpGfapcKO) mice, and found that iron contents decreased in the cerebral cortex and hippocampus of young (6 M) and old (18 M) CpGfapcKO mice. Further experiments revealed that 6 M CpGfapcKO mice exhibited impaired learning and memory function, while 18 M CpGfapcKO mice exhibited improved learning and memory function. Our study demonstrates that astrocytic Cp deletion blocks brain iron influx through the blood-brain-barrier, with concomitantly increased iron levels in brain microvascular endothelial cells, resulting in brain iron deficiency and down-regulation of ferritin levels in neurons, astrocytes, microglia and oligodendrocytes. At the young age, the synapse density, synapse-related protein levels, 5-hydroxytryptamine and norepinephrine, hippocampal neurogenesis and myelin formation were all decreased in CpGfapcKO mice. These changes affected learning and memory impairment in young CpGfapcKO mice. In old CpGfapcKO mice, iron accumulation with aging was attenuated, and was accompanied by the alleviation of the ROS-MAPK-apoptosis pathway, Tau phosphorylation and β-amyloid aggregation, thus delaying age-related memory decline. Overall, our results demonstrate that astrocytic Cp deletion has divergent effects on learning and memory function via different regulatory mechanisms induced by decreased iron contents in the brain of mice, which may present strategies for the prevention and treatment of dementia.

The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain

“…Thus, aged Cp cKO animals exhibit alterations of executive‐level processes, such as short‐term memory. In agreement with our results, Li et al (2022) have recently shown that Cp deletion in GFAP‐positive astrocytes induces learning and memory deficits, reductions in synapse density, and abnormal hippocampal neurogenesis in adult mice. However, they found improved learning and memory functions and reduced brain iron levels in aged Cp‐deficient animals (Li et al, 2022).…”

“…In agreement with our results, Li et al (2022) have recently shown that Cp deletion in GFAP‐positive astrocytes induces learning and memory deficits, reductions in synapse density, and abnormal hippocampal neurogenesis in adult mice. However, they found improved learning and memory functions and reduced brain iron levels in aged Cp‐deficient animals (Li et al, 2022). In our experiments, Cp deletion was induced at specific time‐points and was restricted to only Glast1‐positive astrocytes of the postnatal brain (Cheli et al, 2021; Tran et al, 2018).…”

“…In our experiments, Cp deletion was induced at specific time‐points and was restricted to only Glast1‐positive astrocytes of the postnatal brain (Cheli et al, 2021; Tran et al, 2018). In contrast, in the work of Li et al (2022) Cp was ablated in all GFAP‐positive cells from embryonic stages, potentially creating compensatory effects in aged astrocytes (Garcia et al, 2004; Imura et al, 2003; Malatesta et al, 2003). In summary, we have ablated the Cp gene specifically in astrocytes of the CNS; thus, all the phenotypic changes found in our Cp cKO mouse can be attributed to the absence of Cp activity exclusively in astrocytes.…”

Brain iron acquisition: An overview of homeostatic regulation and disease dysregulation

“…Both Cp and Heph are homologous ferroxidases that aid Fpn in the export of iron from cells, with Heph most commonly found in barrier cells such as ECs (Jiang et al, 2015). Cp is in a glycosylphosphatidylinositol‐anchored form present in astrocytes (Patel & David, 1997) but still vital to brain iron acquisition (Li et al, 2022). Soluble Cp has been implicated in the stimulation of iron release from ECs (McCarthy & Kosman, 2014; Patel et al, 2002).…”

Ferroptosis-Regulated Cell Death as a Therapeutic Strategy for Neurodegenerative Diseases: Current Status and Future Prospects

“…Further research has expounded that astrocytes are essential for iron homeostasis regulation in neurons. Moreover, iron content in astrocytes and microglia is reported to increase with age …”