DHCR24 exerts neuroprotection upon inflammation-induced neuronal death.

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.

• Authors: Henna Martiskainen, Kaisa M A Paldanius, Teemu Natunen, Mari Takalo, Mikael Marttinen, Stina Leskelä, Nadine Huber, Petra Mäkinen, Enni Bertling, Hiramani Dhungana, Mikko Huuskonen, Paavo Honkakoski, Pirta Hotulainen, Kirsi Rilla, Jari Koistinaho, Hilkka Soininen, Tarja Malm, Annakaisa Haapasalo, Mikko Hiltunen
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 14 Issue 1 Pg. 215 (Nov 07 2017) ISSN: 1742-2094 [Electronic] England
• PMID: 29115990 (Publication Type: Journal Article)

Chemical References

• Oxidoreductases Acting on CH-CH Group Donors

Topics

• Animals
• Brain Ischemia (metabolism, pathology)
• Cell Death (physiology)
• Coculture Techniques
• Hippocampus (metabolism, pathology)
• Humans
• Inflammation (metabolism, pathology)
• Male
• Mice
• Microglia (metabolism)
• Neurons (metabolism, pathology)
• Neuroprotection (physiology)
• Oxidoreductases Acting on CH-CH Group Donors (metabolism)