Astrocyte‐specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis

Abstract

Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte‐specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP‐activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.

Astrocyte-derived lactoferrin reduces Aβ burden by promoting the interaction of p38 and PP2A in APP/PS1 transgenic mice

“…Lf is overexpressed in the glial cells and neurons of the elderly person and AD patients (Kawamata et al, 1993;Leveugle et al, 1994), while, to date, the functions of Lf in different cell types remain unexplored. Our recent study exerted that astrocytic Lf knockout impaired the neuronal dendritic complexity and cognitive ability via decreasing cholesterol production during early life in mice (Xu et al, 2022), suggesting the important roles of astrocytes in regulating neuronal functions. Several studies revealed that supplements with Lf effectively retarded AD progression (Abdelhamid et al, 2020;Guo et al, 2017).…”

“…The primary astrocytes were extracted according to our previous study with some modifications (Xu et al, 2022). In this study, wild-type (WT) mice and Astro-Lf mice were employed to obtain the primary astrocytes.…”

Astrocyte‐derived lactoferrin reduces β‐amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice

“…Notably, astrocytic Lf knockout significantly inhibited cholesterol synthesis and reduced APOE expression (Xu et al, 2022), suggesting that Lf overexpression in astrocytes may increase the expression of APOE via modulating cholesterol synthesis. How the astrocytic Lf overexpression promotes APOE up-regulation is an interesting topic, and we hope to uncover the mechanism in our future studies.…”

“…Lf is overexpressed in glial cells and neurons of elderly people and AD patients (Kawamata et al, 1993; Leveugle et al, 1994), although, to date, the functions of Lf in different cell types remain largely unexplored. Astrocytic Lf knockout impaired neuronal dendritic complexity and cognitive ability, by decreasing cholesterol production during early life in mice (Xu et al, 2022), suggesting important roles for astrocytic Lf in regulating neuronal functions. In this study, human Lf overexpression in astrocytes improved the cognitive capacity of APP/PS1 mice and also improved the vision of WT mice, possibly via enhanced brain development caused by Lf‐induced up‐regulation of neuronal connectivity and neurotrophin production (Chen et al, 2015; Schirmbeck et al, 2022).…”

“…Primary astrocytes were extracted according to our previous study, with some modifications (Xu et al, 2022). In this study, wild‐type (WT) mice and Astro‐Lf mice were used to obtain primary astrocytes.…”