Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2

Abstract

Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis. In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health. Results showed that oxysterols present in mild or severe AD brains induce a clear morphological change in mouse primary astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including lipocalin-2 (Lcn2). Moreover, astrocyte conditioned media analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes.

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

“…In line, exogenous cholesterol addition in rat astrocytes triggered astrocyte activation, indicated by upregulation of glial fibrillary acidic protein (GFAP) ( Avila-Muñoz and Arias, 2015 ). Finally, exogenous addition of a mixture of oxysterols, representing oxysterols that are produced when cholesterol accumulates in the AD brain, promote upregulation of reactive astrocyte markers, which contributed to synaptotoxicity ( Staurenghi et al, 2021 ). In microglia, high cholesterol can affect immune function, as particularly studied in respect of cholesterol-rich myelin debris, which promotes inflammatory activation of microglia ( Cantuti-Castelvetri et al, 2018 ).…”

The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

“…This change was accompanied by the up-regulation of some reactive astrocyte markers and the release of pro-inflammatory molecules. Moreover, oxysterol-treated astrocytes have been shown to exert a synaptotoxic effect on mouse primary neurons, mainly mediated by lipocalin 2 release [ 104 ].…”

Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes

“…This protein is involved in several processes including inflammation, iron metabolism, cell death, and cell survival, modulating the cellular response to Aβ [ 275 ]. Staurenghi et al demonstrated that increased levels of oxysterols observed in mild or severe AD brains, accompanied by increased levels of Lcn2, determine a clear morphological change in mouse primary astrocytes [ 276 ]. A recent study found that the iron chelators deferoxamine and deferiprone reduce Aβ-induced iron accumulation in astrocytes and inhibit Aβ-induced Lcn2, suggesting these molecules as promising therapeutic strategies against AD [ 205 ].…”