Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia

Abstract

Stroke is the second leading cause of death and the most frequent cause of adult disability. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischaemia. Although previous studies have demonstrated that Npas4 plays a critical role in protecting neurons against neurodegenerative insults, the neuroprotective effect of Npas4 in response to ischaemic brain injury remains unknown. In this study, we used a loss-of-function approach to examine the neuroprotective potential of Npas4 in the context of ischaemic damage. Using oxygen and glucose deprivation, we demonstrated that the knockdown of Npas4 in mouse cortical neurons resulted in increased susceptibility to cell death. The protective effect of Npas4 was further investigated in vivo using a photochemically-induced stroke model in mice. We found a significantly larger lesion size and increased neurodegeneration in Npas4 knockout mice as compared to wild-type mice. Moreover, we also showed that ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death. Taken together, these data suggest that Npas4 plays a neuroprotective role in ischaemic stroke by limiting progressive neurodegeneration and neuroinflammation.

Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1

“…NPAS4 expression was lower in the cerebellar Purkinje cells of SCA1 mice than those of the WT mice, but this was reversed by treadmill training. Although the regulatory role of NPAS4 in SCA1 remains unclear, the protection of neurons against cerebellar ischemia and neurodegenerative insults in Huntington's disease through upregulated NPAS4 expression were demonstrated. Thus, we suggest that the exercise‐induced increase of cerebellar NPAS4 expression may have reflected the higher neuronal activity in the exercise‐trained SCA1 mice than the nontrained mice.…”

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

“…FGFR1, which spans the cytomembrane, belongs to the receptor tyrosine kinase family. Studies have shown that activating cytomembrane FGFR1 can promote neural stem/progenitor cell proliferation via the PI3K-Akt-β-catenin signaling pathway or the Akt-mammalian target of rapamycin complex 1 signaling pathway, whereas nuclear FGFR1 signaling targets neurogenic and neuronal differentiation genes such as neuroD1, neuroligin, and Stat3 to promote neuronal differentiation and migration [53–56]. In this study, we found that after stroke, both cytomembrane FGFR1 and nuclear FGFR1 were activated, along with increases in expression of PI3K, pAkt, DCX, PSA-NCAM, and Mash1, and proliferation of DCX-positive and GFAP/BrdU-labeled cells in the SVZ.…”

DNA methylation change in neurotrophic genes with aging and delirium evidenced from three independent cohorts

“…Serum levels of the glial cell linederived neurotrophic factor (GDNF) as well as BDNF were decreased in subjects with mild cognitive impairment and Alzheimer's disease [12]. A Neuronal Per-Arnt-Sim domain protein 4 (NPAS4) knockdown mouse model showed increased cell death in cortical neurons [13]. This invivo investigation also revealed an increased lesion size and greater neurodegeneration after a photochemically-induced stroke [13].…”

“…A Neuronal Per-Arnt-Sim domain protein 4 (NPAS4) knockdown mouse model showed increased cell death in cortical neurons [13]. This invivo investigation also revealed an increased lesion size and greater neurodegeneration after a photochemically-induced stroke [13]. The nuclear receptor subfamily 4A2 (NR4A2) critically regulates Alzheimer's disease (AD)-related pathophysiology [14].…”