Biology subjects

Lu, X.-Y.

Publications and source records attributed to Lu, X.-Y..

6 recordsLinked to original sources

bioRxiv2026

Atypical Chemokine Receptor DARC/ACKR1 Is Expressed Selectively by Neurons with Regional Heterogeneity and Protects against Neuroinflammation and Cognitive Impairment

Atypical chemokine receptors (ACKRs) regulate inflammatory responses by scavenging and sequestering chemokines. The Duffy antigen receptor for chemokines (DARC), also known as ACKR1, binds multiple inflammatory chemokines and regulates inflammation in peripheral tissues. However, the distribution and functional role of DARC/ACKR1 in the brain remain to be defined. Here, we show that DARC/ACKR1 is widely expressed throughout the mouse brain, with marked regional heterogeneity. DARC/ACKR1 is predominantly expressed by neurons and is not detected in microglia or astrocytes. Importantly, this neuronal expression pattern was also observed in the human brain. Furthermore, DARC/ACKR1 deficiency resulted in enhanced neuroinflammation, characterized by increased microglial activation and astrogliosis across multiple brain regions, particularly the hippocampus, and was accompanied by cognitive deficits. Together, these findings identify DARC/ACKR1 as a previously unrecognized neuron-specific atypical chemokine receptor that plays an important role in restraining neuroinflammation and preserving cognitive function.

neuroscience↗

bioRxiv2026

Activation of DMH GABAergic neurons, but not local GABAergic AgRP neurons, attenuates chronic stress-induced POMC neuron hyperactivity

Identifying the neural circuits engaged and reshaped by chronic stress is critical for understanding how adaptive responses shift to maladaptive behaviors that contribute to stress-related disorders. Our previous work demonstrates that chronic unpredictable stress (CUS) induces a persistent increase in the firing activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). This hyperactivity is due, in part, to a reduction in GABAergic synaptic transmission onto POMC neurons, indicating a disruption in inhibitory control. However, the sources of GABAergic inputs responsible for this effect of chronic stress are unknown. Although AgRP neurons provide local GABAergic input onto POMC neurons and are suppressed by chronic stress, chemogenetic activation of AgRP neurons during stress exposure failed to reduce POMC neuron hyperactivity. GABAergic projections originating from the dorsomedial hypothalamus (DMH) represent another source of inhibitory input to POMC neurons. We found that CUS decreased the firing activity of DMH GABAergic neurons with sex differences, with females exhibiting greater vulnerability to stress-induced suppression. Chemogenetic activation of these neurons during chronic stress markedly attenuated POMC neuron hyperactivity in both sexes, indicating that DMH GABAergic neurons function as a critical upstream regulator of POMC neuron activity under chronic stress. These findings suggest that reduced inhibitory input from DMH GABAergic neurons, rather than local GABAergic AgRP neurons, drives POMC neuron hyperactivity. The weakening of the DMHGABA[->]ARCPOMC circuit activity may represent a novel mechanism underlying maladaptive stress responses and a potential therapeutic target for stress-related disorders.

neuroscience↗

bioRxiv2025

Neuronal HDAC9: A key regulator of cognitive and synaptic aging, rescuing Alzheimer's disease-related phenotypes

Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimers disease (AD). As major regulators of epigenetic processes, histone deacetylases (HDACs) have emerged as potential therapeutic targets for cognitive enhancement in neurodegenerative diseases. However, the distinct roles of individual HDAC isoforms remain to be defined. Here, we report that HDAC9 is specifically expressed in neurons of human and mouse brains, and its expression declines with age. HDAC9 deficiency impairs cognitive function and synaptic plasticity in young mice. Selective deletion of HDAC9 in hippocampal CA1 neurons also induces cognitive impairment. In contrast, overexpression of HDAC9 in forebrain glutamatergic neurons preserves cognitive function in aged mice. Moreover, HDAC9 is also downregulated in the brain of AD mouse models, whereas neuronal overexpression of HDAC9 alleviates AD-related cognitive and synaptic deficits and reduces A{beta} deposition. Together, these findings suggest neuronal HDAC9 is necessary and sufficient for maintaining cognitive and synaptic functions in the context of aging and AD.

neuroscience↗

bioRxiv2022

Cholinergic forebrain activation improves cognition, boosts neurotrophin receptors, and lowers Aβ42 levels in the cerebral cortex of 5xFAD mice.

The biological basis of Alzheimers dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms reflecting the neuropathologies surrounding beta amyloid and tau. To shed light on the contributions of these different biological elements, we performed five month intermittent stimulation of the basal forebrain, which projects to the cortical mantle, in 5xFAD Alzheimers model mice and wild-type littermates, and subjected mice to behavioral testing and tissue analysis. The 5xFAD mice performed worse in water maze testing than their littermates. Stimulation improved both classes of mice, and removed performance differences between genotypes by the fifth testing day. Stimulated groups had two to four-fold increases in immunoblot measures of each of the neurotrophin receptors tropomyosin receptor kinase A and B. Stimulation also led to lower tissue A{beta}42 and beta amyloid cleavage enzyme 1 in 5xFAD mice. Despite the lack of strong direct projections from the basal forebrain stimulation region to the hippocampus, the hippocampal tissues in stimulated mice had more nerve growth factor receptor, and lower levels of beta secretase for amyloid. These data support a causal relation between forebrain cholinergic pathways and cognitive decline dependent on A{beta}42. Activation of cholinergic brain pathways improves neurotrophin pathways and reduces A{beta}42 accumulation. The recruitment of both classes of neurotrophin receptors in the process suggests a serine protease cleavage intermediary between cholinergic response and neurotrophin activation.

neuroscience↗

bioRxiv2020

HSC70, HSPA1A, and HSP90AB1 Facilitate Ebola Virus trVLPs to Induce Autophagy

Ebola virus (EBOV) can induce autophagy to benefit the virus life cycle, but detailed mechanisms remain to be elucidated. We previously found that EBOV GP and VP40 proteins interact with HSC70 (HSPA8), HSPA1A, and HSP90AB1. Thus, we presumed that EBOV likely induced autophagy by virus protein-host HSC70 or co-chaperon interactions via chaperone-mediated autophagy (CMA). We developed EBOV-trVLPs to model the EBOV life cycle, infected 293T cells with trVLPs, evaluated CMA by GFP-LC3 and RFP-LAMP1 co-localization, transmission electron microscopy (TEM) observation, and immunoblot analysis. The results demonstrated that EBOV-trVLPs induce autophagy which could not be inhibited by 3-MA significantly; autophagosomes and autolysosomes are obviously in the cytoplasm confirming CMA in cells infected with trVLPs. Meanwhile, a knockdown of HSC70 and relevant co-chaperones could inhibit trVLPs-associated autophagy, but no effort to Akt/mTOR/PHLPP1 pathway. These data indicate that EBOV-trVLPs could induce autophagy by CMA but was not limited by the CMA pathway. HSC70, HSPA1A, and HSP90AB1 participate and regulate CMA induced by EBOV-trVLPs. This was the first study about EBOV-trVLPs-induction of CMA and provides insight into the viral protein-host protein interaction, which is probably associated with CMA. HighlightsO_LIEBOV-trVLPs induce chaperone-mediated autophagy (CMA) but are not limit by CMA. C_LIO_LIHSC70, HSPA1A, and HSP90AB1 facilitate EBOV-trVLPs to induce autophagy C_LIO_LIKnockdown of HSC70, HSPA1A, and HSP90AB1 inhibit EBOV-trVLPs-induced CMA. C_LI

molecular biology↗

bioRxiv2018

Circular RNAs regulate cancer stem cells by FMRP against CCAR1 complex in hepatocellular carcinoma

Circular RNA (circRNA) possesses great pre-clinical diagnostic and therapeutic potentials in multiple cancers. However, the underlying correlation between circRNAs and cancer stem cells (CSCs) has not been reported. The absence of circZKSCAN1 endowed several malignant properties including cancer stemness and tightly correlated with worse overall and recurrence-free survival rate in HCC cells in vitro and in vivo. Bioinformatics analysis and RNA immunoprecipitation-sequencing (RIP-seq) results revealed that circZKSCAN1 exerted its inhibitive role by competitively binding FMRP, therefore, block the binding between FMRP and {beta}-catenin-binding protein-cell cycle and apoptosis regulator 1 (CCAR1) mRNA, and subsequently restraining the transcriptional activity of Wnt signaling. In addition, RNA-splicing protein Quaking 5 was found downregulated in HCC tissues and responsible for the reduction of circZKSCAN1. Collectively, this study revealed the mechanisms underlying the regulatory role of circZKSCAN1 in HCC CSCs and identified the newly discovered Qki5- circZKSCAN1-FMRP-CCAR1-Wnt signaling axis as a potentially important therapeutic target for HCC treatment.\n\nStatement of significanceO_LICircZKSCAN1, a novel negative regulator for cancer stem cells, was firstly identified with reverse correlation with HCC prognosis.\nC_LIO_LICircZKSCAN1 directly targets FMRP, and competitive binding with {beta}-catenin-binding protein cell cycle and apoptosis regulator 1 (CCAR1) for its activity.\nC_LIO_LIThe decreased expression of Quaking 5 is responsible for the absence of circZKSCAN1 in HCC.\nC_LI

cancer biology↗