Journal of Neurochemistry最新文献

Mutations in the Transcription Factor 20 (TCF20) have been identified in patients with autism spectrum disorders (ASDs), intellectual disabilities (IDs), and other neurological issues. Recently, a new syndrome called TCF20-associated neurodevelopmental disorders (TAND) has been described, with specific clinical features. While TCF20's role in the neurogenesis of mouse embryos has been reported, little is known about its molecular function in neurons. In this study, we demonstrate that TCF20 is expressed in all analyzed brain regions in mice, and its expression increases during brain development but decreases in muscle tissue. Our findings suggest that TCF20 plays a central role in dendritic arborization and dendritic spine formation processes. RNA sequencing analysis revealed a downregulation of pre- and postsynaptic pathways in TCF20 knockdown neurons. We also found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates and in synaptosomal preparations of knockdown TCF20 rat cortical cultures. Furthermore, synaptosomal preparations of knockdown TCF20 rat cortical cultures showed significant downregulation of GluN2B and GABRA5, while GluA2 was significantly upregulated. Overall, our data suggest that TCF20 plays an essential role in neuronal development and function by modulating the expression of proteins involved in dendrite and synapse formation and function.

Brain damage induced by ischemia promotes the development of cognitive dysfunction, thus increasing the risk of dementia such as Alzheimer's disease (AD). Studies indicate that cellular acidification-triggered activation of asparagine endopeptidase (AEP) plays a key role in ischemic brain injury, through multiple molecular pathways, including cleavage of its substrates such as SET (inhibitor 2 of PP2A, I₂^PP2A) and Tau. However, whether direct targeting AEP can effectively prevent post-stroke cognitive impairment (PSCI) remains unanswered. Here, we explored the therapeutic effect and underlying mechanism of the AEP inhibitor AENK on cognitive impairment of the rats with middle cerebral artery occlusion (MCAO) and on neuronal damage in cultured primary neurons exposed to oxygen and glucose deprivation (OGD). We found that the administration of AENK significantly reduces activated AEP levels in ischemic rat brains, attenuates cognitive deficits, and rescues synaptic dysfunction. For the mechanism, with AEP inhibition, cleavage of SET, inhibition of protein phosphatase 2A (PP2A), and Tau hyperphosphorylation resulted from PP2A inhibition, were all completely or partially reversed. In primary neurons, AENK effectively prevents AEP activation, SET cleavage and cytoplasmic retention, tau hyperphosphorylation and synaptic damage induced by OGD. We conclude that AENK ameliorates cognitive impairment and prevents tau hyperphosphorylation, through inhibiting AEP-mediated cleavage of SET in ischemic brain injury, and direct inhibition of AEP might be a potential therapeutic strategy for preventing synaptic damage and cognitive impairment after stroke.

Severe trauma frequently leads to nerve damage. Peripheral nerves possess a degree of regenerative ability, and actively promoting their recovery can help restore the sensory and functional capacities of tissues. The neuropeptide calcitonin gene-related peptide (CGRP) is believed to regulate the repair of injured peripheral nerves, with neuronal transient receptor potential vanilloid type 1 (TRPV1) potentially serving as a crucial upstream factor. In this study, we established a mouse model of sciatic nerve (SN) crush injury and found that intrathecal injection of capsaicin (Cap) activated the neuronal TRPV1-CGRP axis, thereby promoting SN repair. Conversely, the application of capsazepine (Cpz), which inhibits the neuronal TRPV1-CGRP axis, delayed SN repair. Local restoration of CGRP expression at the injury site enhanced the repair process. In vitro experiments, we employed the rat Schwann cell (SC) line RSC96 to establish an indirect co-culture model of neurons and SCs. We observed that the proliferation, migration, expression of myelination-associated proteins, and neurotrophic secretion functions of RSC96 cells are positively correlated with the degree of activation of neuronal TRPV1. Inhibition of neuronal TRPV1, followed by the restoration of CGRP levels, improved these functions in RSC96 cells. Furthermore, activation of the neuronal TRPV1-CGRP axis resulted in an upregulation of extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation levels and an increase in hypoxia-inducible factor 1α (HIF-1α) accumulation in RSC96 cells, thereby promoting their proliferation and migration. In summary, this study demonstrates that neuronal TRPV1-CGRP axis can regulate biological behavior of SCs and axon regeneration by activating the ERK/HIF-1 signaling pathway following peripheral nerve injury. This finding clarifies the role of CGRP in neuroregulatory networks and provides a novel reference point for the development of drugs and biomaterials for treating nerve damage.

The adult central nervous system (CNS) hosts several niches, in which the neural stem and precursor cells (NPCs) reside. The subventricular zone (SVZ) lines the lateral brain ventricles and the subgranular zone (SGZ) is located in the dentate gyrus of the hippocampus. SVZ and SGZ NPCs replace neurons and glia in the homeostatic as well as diseased or injured states. Recently, NPCs have been found to express neurotransmitter receptors, respond to electrical stimulation and interact with neurons, suggesting that neuron-NPC communication is an emerging critical regulator of NPC biology. In this review, we discuss reports that demonstrate neuronal innervation and control of the neurogenic niches. We discuss the role of innervating neurons in regulating NPC fates, such as activation, proliferation, and differentiation. Our review focuses primarily on the innervation of the SVZ niche by the following neuronal types: glutamatergic, GABAergic projection and interneurons, cholinergic, dopaminergic, serotonergic, neuropeptidergic, nitrergic, and noradrenergic. We also discuss the origins of SVZ niche innervating neurons, such as striatum, cortex, basal ganglia, raphe nuclei, substantia nigra and ventral tegmental area, hypothalamus, and locus coeruleus. Our review highlights the various roles of innervating neurons in SVZ NPC fates in a spatiotemporal manner and emphasizes a need for future investigation into the impact of neuronal innervation on NPC gliogenesis.

The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein found in microglia within the brain, and its soluble form (sTREM2) has been shown to reduce amyloid deposition. Whether elevated TREM2-mediated microglial activity decreases the risk of Alzheimer's disease (AD) is unclear. The aim of this study was to assess whether high cerebrospinal fluid (CSF) levels of sTREM2 attenuate the risk of APOE ε4-associated amyloid pathology. We included 877 cognitively intact subjects from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, including APOE ε4 carriers (n = 136) and non-carriers (n = 741). The linear regression was used to examine the interaction effect between CSF sTREM2 levels and APOE ε4 status on CSF Aβ42 levels. Additionally, subgroup analyses stratified by sex and age were conducted. Our main finding was that higher concentrations of CSF sTREM2 attenuated the effect of APOE ε4 carriage (i.e., the sTREM2 × APOE ε4 interaction) on amyloid deposition (β = −2.701e-05, p = 0.023). Subgroup analyses showed that the effect of interaction was still significant only in male (p = 0.041) and mid-life (p = 0.013) subgroups. Our study suggested that in cognitively intact individuals, changes in sTREM2 levels are associated with biomarkers of AD, and higher concentrations of CSF sTREM2 attenuated the risk of APOE ε4-related amyloid pathology. The identified role of the sTREM2 × APOE ε4 interaction in amyloid pathology offers new insights into potential strategies for AD prevention in APOE ε4 carriers.