Abstract
BackgroundDHCR24, 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.MethodsHere, 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.ResultsOverexpression 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.ConclusionsThese results suggest that the augmentation of DHCR24 levels provides neuroprotection in acute stress conditions, which lead to neuronal loss in vitro and in vivo.
Highlights
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
Decreased levels of DHCR24 lead to the stabilization of BACE1 and to increased β-amyloidogenic processing of amyloid precursor protein (APP) under apoptotic conditions in vitro [18]. These findings suggest that augmentation of DHCR24 levels in the affected brain areas might provide a potential therapeutic approach to intervene in Alzheimer’s disease (AD) pathogenesis
We utilized co-cultures prepared from embryonic mouse primary cortical neurons and mouse BV2 microglial cells, which were treated with LPS and interferon γ (IFN-γ) to induce neuroinflammation at 5 days in vitro according to [19]
Summary
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. Decreased levels of DHCR24 lead to the stabilization of BACE1 and to increased β-amyloidogenic processing of APP under apoptotic conditions in vitro [18]. These findings suggest that augmentation of DHCR24 levels in the affected brain areas might provide a potential therapeutic approach to intervene in AD pathogenesis
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