27-Hydroxycholesterol Induces Aberrant Morphology and Synaptic Dysfunction in Hippocampal Neurons

Abstract

Hypercholesterolemia is a risk factor for neurodegenerative diseases, but how high blood cholesterol levels are linked to neurodegeneration is still unknown. Here, we show that an excess of the blood–brain barrier permeable cholesterol metabolite 27-hydroxycholesterol (27-OH) impairs neuronal morphology and reduces hippocampal spine density and the levels of the postsynaptic protein PSD95. Dendritic spines are the main postsynaptic elements of excitatory synapses and are crucial structures for memory and cognition. Furthermore, PSD95 has an essential function for synaptic maintenance and plasticity. PSD95 synthesis is controlled by the REST–miR124a–PTBP1 axis. Here, we report that high levels of 27-OH induce REST–miR124a–PTBP1 axis dysregulation in a possible RxRγ-dependent manner, suggesting that 27-OH reduces PSD95 levels through this mechanism. Our results reveal a possible molecular link between hypercholesterolemia and neurodegeneration. We discuss the possibility that reduction of 27-OH levels could be a useful strategy for preventing memory and cognitive decline in neurodegenerative disorders.

Oxysterols Present in Alzheimer’s Disease Braininduce Synaptoxicity by Activating Astrocytes: A Major Role for Lipocalin-2

“…Moreover, when neurons were directly treated with oxysterols, PSD95 (P<0.05), cleaved caspase-3 (P<0.01), and synapsin levels (P<0.05) were all significantly altered (Fig. 5B), confirming previous results showing that oxysterols directly compromise neuron health [31,33]. Importantly, all these results were obtained in the absence of significant neuronal death, as assessed by LDH release (Supplemental Fig.…”

“…Concerning oxysterols, it has been demonstrated that 27-OHC reduces dendritic spine density and PSD95 levels in primary mouse hippocampal neurons [33], whereas 24-OHC affects synaptic plasticity via modulation of NMDAR [79]. Since oxysterols are able to directly modulate several pathways involved in PSD95 regulation [50], other oxysterols present into the mixture could be involved in the observed PSD95 reduction, even if their role needs further investigation.…”

“…These and other data highlight that neuronal caspase-3 can be activated by extracellular inflammatory mediators. Caspase-3 can also be activated by oxysterols, mainly those oxidized at C7 position but also others [33,50,[85][86][87].…”

“…3). Since these oxysterols are known to directly affect neuron viability [31,33,50], we co-cultured neurons with astrocytes that had been pre-treated with oxysterols. As shown in Figure 5A, astrocytes grown on cell culture inserts were pre-treated for 12h with the Late AD oxysterol mixture (10 µM) and then transferred to culture plates containing neurons for a further 24h: this allowed us to investigate the effect of mediators released from stimulated astrocyte on neurons, without transferring oxysterols that remained in ACM.…”

“…The effects of oxysterols are still controversial but growing evidence suggests that some of them (e.g. 27-OHC, 7-KC, 7-and 7-OHC) may play a role in AD pathogenesis by inducing oxidative stress, inflammation [29], Aβ formation and accumulation [30,31], tau hyperphosphorylation [32], synaptic dysfunction [33], and cell death [34,35].…”