Lipocalin 2 modulates the cellular response to amyloid beta

Abstract

The production, accumulation and aggregation of amyloid beta (Ab) 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 Ab aggregation. Herein, we describe that lipocalin 2 (LCN2), a mammalian acute-phase protein involved in iron homeostasis, is highly produced in response to Ab 1-42 by choroid plexus epithelial cells and astrocytes, but not by microglia or neurons. Although Ab 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 Ab toxicity to astrocytes requires LCN2, which represents a novel mechanism to target when addressing AD.

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…Robust increased NGAL protein levels were found in AD post-mortem human brain tissue [184], a mouse model for MS [186], and mouse model for cerebral ischemia [187]. Increased NGAL protein levels are detrimental to neuronal health [188] and sensitize neurons and other brain cell types to cell death upon exposure to Aβ and oxidative stress [184,189,190]. In addition, NGAL was shown to further promote pro-inflammatory reactions, and to stimulate classical inflammatory activation of microglia and astrocytes [191,192].…”

Insights on the pathophysiology of Alzheimer's disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system

“…Altogether, these might aggravate the pro-inflammatory profile and overall CNS pathology in AD (Medeiros and LaFerla, 2013;Sofroniew and Vinters, 2010). Of note, as referred before, LCN2 was shown to be overproduced also by astrocytes, in vitro, in response to Aβ peptides (Mesquita et al, 2014) and to be increased in the brain of AD patients (Naude et al, 2012). Moreover, it was recently shown that increased levels of LCN2…”

“…of AD. Of note, it was shown that AD patients present altered levels of LCN2 in the CSF (Naude et al, 2012), and that LCN2 is involved in the in vitro pro-inflammatory response to increased level of Aβ peptides, displaying a detrimental effect on brain cell survival (Mesquita et al, 2014). Considering this new evidence, it will be important to further elucidate the role of LCN2 in the context of an in vivo model of AD.…”

“…Particularly in AD, the BCSFB suffers alterations not only due to increased levels of toxic Aβ(Chalbot et al, 2011;Vargas et al, 2010), but also promoted by different blood-born inflammatory molecules and immune cells(Baruch et al, 2015;Schwartz and Baruch, 2014b).Altogether, this altered inflammatory profile at the BCSFB impacts on the CSF-ISF nexus and, consequently, on brain homeostasis and on neurodegeneration(Baruch and Schwartz, 2013;Chalbot et al, 2011;Iliff et al, 2012). Moreover, aging-associated alterations in the secretion of inflammatory molecules by the cells that compose the CP tissue, either by the epithelial or the stromal cells, is viewed as a critical turning point for deficits in brain cell function and plasticity, and were shown to affect processes like glial activation, neurogenesis and cell survival(Baruch et al, 2014;Baruch et al, 2013;Kunis et al, 2013;Villeda et al, 2011).Regarding the inflammatory response in the context of AD-associated pathology, we recently found that the CP epithelial cells overexpress the gene encoding for lipocalin 2 (LCN2) upon stimulation with Aβ peptides(Mesquita et al, 2014). Of interest, LCN2 is involved in the innate immune response(Devireddy et al, 2005; Flo et al, 2004) and its up-regulation is indicative of a rapid pro-inflammatory profile build-up at the CP(Marques et al, 2008;Marques et al, 2009).…”

“…Recent studies have highlighted the alterations observed at the level of the choroid plexus (CP), which forms the BCSFB, and their impact on brain function in aging and inAD (Baruch et al, 2014;Baruch et al, 2013; Baruch et al, 2015;Mesquita et al, 2014;Mesquita et al, 2015). The CP is formed by a monolayer of epithelial cells bound together by tight junctions, which are formed by claudins and occludins present in the lateral side of the apical membrane(Ek et al, 2003;Wolburg et al, 2001).…”