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J Neuroinflammation. 2017 Nov 7;14(1):215. doi: 10.1186/s12974-017-0991-6.

DHCR24 exerts neuroprotection upon inflammation-induced neuronal death.

Author information

1
Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
2
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
3
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
4
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
5
Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
6
Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
7
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. annakaisa.haapasalo@uef.fi.
8
Department of Neurology, Kuopio University Hospital, Kuopio, Finland. annakaisa.haapasalo@uef.fi.
9
Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. mikko.hiltunen@uef.fi.
10
Department of Neurology, Kuopio University Hospital, Kuopio, Finland. mikko.hiltunen@uef.fi.

Abstract

BACKGROUND:

DHCR24, involved in the de novo synthesis of cholesterol and protection of neuronal cells against different stress conditions, has been shown to be selectively downregulated in neurons of the affected brain areas in Alzheimer's disease.

METHODS:

Here, we investigated whether the overexpression of DHCR24 protects neurons against inflammation-induced neuronal death using co-cultures of mouse embryonic primary cortical neurons and BV2 microglial cells upon acute neuroinflammation. Moreover, the effects of DHCR24 overexpression on dendritic spine density and morphology in cultured mature mouse hippocampal neurons and on the outcome measures of ischemia-induced brain damage in vivo in mice were assessed.

RESULTS:

Overexpression of DHCR24 reduced the loss of neurons under inflammation elicited by LPS and IFN-γ treatment in co-cultures of mouse neurons and BV2 microglial cells but did not affect the production of neuroinflammatory mediators, total cellular cholesterol levels, or the activity of proteins linked with neuroprotective signaling. Conversely, the levels of post-synaptic cell adhesion protein neuroligin-1 were significantly increased upon the overexpression of DHCR24 in basal growth conditions. Augmentation of DHCR24 also increased the total number of dendritic spines and the proportion of mushroom spines in mature mouse hippocampal neurons. In vivo, overexpression of DHCR24 in striatum reduced the lesion size measured by MRI in a mouse model of transient focal ischemia.

CONCLUSIONS:

These results suggest that the augmentation of DHCR24 levels provides neuroprotection in acute stress conditions, which lead to neuronal loss in vitro and in vivo.

KEYWORDS:

Alzheimer’s disease; DHCR24/Seladin-1; Neuroinflammation; Neuroprotection

PMID:
29115990
PMCID:
PMC5678793
DOI:
10.1186/s12974-017-0991-6
[Indexed for MEDLINE]
Free PMC Article

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