24(S)-Hydroxycholesterol as a Modulator of Neuronal Signaling and Survival

Abstract

The major cholesterol metabolite in brain, 24(S)-hydroxycholesterol (24S-HC), serves as a vehicle for cholesterol removal. Its effects on neuronal function, however, have only recently begun to be investigated. Here, we review that nascent work. Our own studies have demonstrated that 24S-HC has potent positive modulatory effects on N-methyl-d-aspartate (NMDA) receptor (NMDAR) function. This could have implications not only for brain plasticity but also for pathological NMDAR overuse. Other work has demonstrated effects of 24S-HC on neuronal survival and as a possible biomarker of neurodegenerative disease. Depending on circumstances, both upregulation/mimicry of 24S-HC signaling and down-regulation/antagonism may have therapeutic potential. We are interested in the possibility that synthetic analogues of 24S-HC with positive effects at NMDARs may hold neurotherapeutic promise, given the role of NMDA receptor hypofunction in certain neuropsychiatric disorders.

Keywords: Alzheimer’s disease; NMDA; apoptosis; cholesterol. 24(S)-hydroxycholesterol; glutamate.

Figure 1

Structures of cholesterol (A) and 24S-HC (B). Numbers of select carbons on the steroid rings and side-chain have been labeled. C and D show structures of two synthetic 24S-HC analogues with positive modulatory effects on NMDARs.

Figure 2

Nissl stain (A) and expression heat map for CYP46A1 mRNA expression (B) in coronal brain sections of mouse, showing strong neuronal expression. Images are taken from the Allen Brain Atlas, ©2014 Allen Institute for Brain Science. Allen Mouse Brain Atlas, available from http://mouse.brainmap.org/. C. Schematic of neuronal production of 24S-HC from endoplasmic reticulum and subsequent release. For simplicity, interaction of 24S-HC with only two targets is shown: LXR/RXRs of neurons and astrocytes and NMDARs on neuronal plasma membrane.

Figure 3

Modulation of NMDAR function, synaptic plasticity, and behavior. A. Examples of the effect of 24S-HC at varied concentrations on responses of a cultured hippocampal neuron to NMDA application. B. The concentration response relationship derived from experiments like that in A. The synthetic analogue SGE-201 shows higher potency for positive modulation. C, D. Synaptic efficacy, monitored by field EPSP slope was unchanged after high frequency stimulation 2 hr following ketamine exposure. HFS is typically sufficient to induce long-term potentiation (LTP) of the EPSP slope, but ketamine treatment prevents this. 0.5 μM 24S-HC or 0.5 μM SGE-201 overcomes the inhibition of LTP. E. Plasma levels of SGE-201 and SGE-301 following the indicated i.p. doses. The inset shows brain levels 60 min following administration. Figures panels are adapted from (Paul and others 2013). F. Spontaneous alternations are reduced by MK 801, a psychotomimetic NMDAR antagonist, and the MK 801 effect is partially abrogated by systemic SGE-301 at the indicated doses.

Figure 4

Antagonism of oxysterol positive modulation by another side-chain oxysterol, 25-HC. A. Top panel: example of effect of SGE-201 (0.2 μM) on neuronal response to NMDA application (horizontal bar). Bottom panel: block of SGE-201’s effect by 10 μM 25-HC. B. Effect of varied 25-HC concentrations on the potentiated NMDA response. NMDA current in the absence of modulator is indicated by the dotted line. Figure is adapted from (Linsenbardt and others 2014) and used with permission from Elsevier.

Figure 5

Interaction between positive modulators of NMDAR activity and NMDAR channel blockers. A–C. Effects of the 24S-HC analogue SGE-201 on neuronal activity can be accounted for by effects on NMDAR activity. A, B Raster plots of action potential activity in a dissociated hippocampal culture on a multi-electrode array. The y axis represents the electrodes. C. Under baseline conditions SGE-201 increases spiking activity (ASDR) by >2 fold (blue bar), but no significant increase occurs in the presence of 20 μM MK-801 (open bar), an NMDAR antagonist. D–G. In the presence of positive modulator, the open-channel blockers memantine and ketamine reduce activity. G. Summary data showing that in the absence of SGE-201 (Control), the reduction in activity by the two channel blockers is indistinguishable. In the presence of SGE-201, the effect of the more voltage-sensitive compound memantine is relieved more than that of ketamine. Figure is adapted from (Emnett and others 2014) and used with permission.