Lipocalin 2 modulates the cellular response to amyloid beta

The production, accumulation and aggregation of amyloid beta (Aβ) peptides in Alzheimer''s disease (AD) are influenced by different modulators. Among these are iron and iron-related proteins, given their ability to modulate the expression of the amyloid precursor protein and to drive Aβ aggregation. Herein, we describe that lipocalin 2 (LCN2), a mammalian acute-phase protein involved in iron homeostasis, is highly produced in response to Aβ_1-42 by choroid plexus epithelial cells and astrocytes, but not by microglia or neurons. Although Aβ_1-42 stimulation decreases the dehydrogenase activity and survival of wild-type astrocytes, astrocytes lacking the expression of Lcn2 are not affected. This protection results from a lower expression of the proapoptotic gene Bim and a decreased inflammatory response. Altogether, these findings show that Aβ toxicity to astrocytes requires LCN2, which represents a novel mechanism to target when addressing AD.One of the pathological hallmarks of Alzheimer''s disease (AD) is the increased production and accumulation of amyloid beta (Aβ) peptides in the brain, which result from the misprocessing of the membrane amyloid precursor protein. Through an unidentified combination of events, Aβ peptides, initially soluble, aggregate into oligomers, which are highly toxic to brain cells. Oligomers of Aβ ultimately deposit in different brain regions and form amyloid plaques.¹ The steps that drive the amyloidogenic pathway are still unclear, but the aggregation of Aβ into dimers, trimers and other toxic oligomeric forms seems to be decisive. This process was shown to be influenced by many factors, among which is iron, described to favor the formation and stabilization of toxic Aβ oligomers.^{2, 3} Notably, iron accumulates with age in brain areas that are preferentially affected in AD patients, such as the hippocampus and the cortex.⁴ In these areas, iron and iron-binding proteins were shown to accumulate in the amyloid plaques.⁵ Interestingly, recent evidence points to alterations in the level of iron metabolism-related proteins, such as ferritin, and their impact on iron homeostasis as probable causes of increased amyloid precursor protein expression and misprocessing, as well as increased aggregation of Aβ into toxic oligomers.^{6, 7}Recently, the iron-associated protein lipocalin 2 (LCN2) was implicated in AD.⁸ LCN2, a member of the lipocalin family of soluble proteins, was originally identified as a constituent of granules in human neutrophils.⁹ It was first described as an acute-phase protein¹⁰ able to bind and sequester bacterial iron-loaded siderophores, thus preventing the growth and dissemination of the infectious agents.¹¹ In addition, LCN2 has been described also to mediate transferrin-independent iron delivery^{12, 13} and removal from cells,¹⁴ which is associated with cell proliferation and apoptosis, respectively. Although the pathway through which LCN2 influences cell proliferation remains uncertain, LCN2-mediated apoptosis involves the proapoptotic protein BCL2-like 11 (BCL2L11 or BIM).^{14, 15} Of notice, different cells from the central nervous system (CNS), namely choroid plexus (CP) epithelial cells and astrocytes, have been shown to produce LCN2 in response to various stimuli.^{15, 16, 17, 18, 19} Importantly, a recent study demonstrated that LCN2, produced in response to tumor necrosis factor (TNF), is able to interfere with TNF receptor protective signaling and to enhance the toxicity of glutamate and Aβ.⁸ The present study investigated the mechanism through which LCN2 contributes to the modulation of brain cell metabolism and survival in response to Aβ.