Lipocalin-2 (LCN2) has been implicated in the pathogenesis of sepsis-associated encephalopathy (SAE). Our previous work demonstrated a significant increase in astrocyte-derived LCN2 in the hippocampal region during SAE. Notably, this elevated expression strongly correlates with neuronal loss and cognitive impairment, although the underlying mechanisms remain elusive. In our study, we demonstrate that increased secretion of LCN2 from hippocampal astrocytes in SAE mice binds to the neuronal receptor 24p3R, thereby inducing neuronal damage. Notably, the downregulation of neuronal 24p3R effectively abolished the detrimental effects of LCN2. In both lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced sepsis models in C57 mice, neuronal 24p3R knockdown similarly alleviated sepsis-induced synaptic dysfunction and cognitive deficits. Moreover, elevated brain LCN2 levels during sepsis coincided with suppressed autophagy. Mechanistic studies revealed that LCN2-24p3R axis activated the neuronal mTOR-ULK1 pathway, leading to inhibition of autophagy. Importantly, the inhibition of neuronal mTOR activity restored autophagy and ameliorated mitochondrial damage and neuronal loss caused by astrocyte-derived LCN2. These findings suggest an etiopathogenic mechanism of SAE, which is initiated by the increased astrocytic secretion of LCN2, acting on neuronal 24p3R to activate the mTOR-ULK1 pathway, suppress autophagy, and promote mitochondrial dysfunction and neuronal loss, ultimately driving SAE progression. This study provides novel insights into the molecular mechanisms of astrocyte-neuron communication in SAE and identifies potential therapeutic targets for effective intervention.

Mitophagy is a conserved cellular process that removes dysfunctional or excess mitochondria. Increasing evidence suggests that impaired mitophagy plays a crucial role in AD development. Promoting mitophagy has been shown to be protective in models of AD, representing an important target of Alzheimer's disease (AD). However, the molecular mechanisms underlying impaired mitophagy in AD are still elusive. Here, we provide evidence that highly expressed acylglycerol kinase (AGK), a mitochondrial lipid kinase associated with mitochondrial protein transport, glycolysis, and platelet formation, is a key mediator of mitophagy in AD. We found that AGK promoted the binding of ATPase family AAA domain containing 3A to translocase of the inner mitochondrial membrane 23 and sequentially increased mitochondrial import of PTEN-induced putative kinase 1, leading to the decrease of mitophagy. Further investigations revealed that the AGK downregulation in neuronal cells and APP/PS1 mice enhanced mitophagy, increased mitochondrial membrane potential, decreased pathological Tau/Aβ and neuroinflammation, and alleviated cognitive dysfunctions in the mice. Altogether our findings indicate that AGK plays a critical role in mediating mitophagy defects in AD; furthermore, downregulation of AGK promotes mitophagy and the decrease of Aβ and pathological Tau, providing an encouraging therapeutic treatment for AD.

The offspring has different responses to maternal prenatal stress, some susceptible ones exhibit depression or anxiety-like behavior, and some ones demonstrate resilience and do not go on to develop behavior disorders. However, the mechanism underlying the resilience in the offspring to maternal prenatal stress remains unclear. In this study, we aimed to explore whether BMP4 signaling was associated with resilience to depression in the offspring following maternal prenatal stress, and further to explore whether inhibition of BPM4 signaling could promote resilience to depression in the offspring. The pregnant rats were performed mild restraint stress model. After delivery, sucrose preference test, open field test and forced swimming test were used to assess susceptibility or resilience in the offspring. BMP4 inhibitor noggin was administrated to inhibit BMP4 signaling. Hippocampal BMP4- phospho-Smad1/5/8-Id2 signaling and noggin level were measured by RT-PCR and Western Blot Analysis. Immunohistochemistry was used to measure the hippocampal neurogenesis. We found that hippocampal BMP4, phospho-Smad1/5/8 and Id2 level in susceptible offspring rats were significantly higher than that in resilience group. There was less number of BrdU+/NeuN+ positive cells in the dentate gyrus of the hippocampus in susceptible offspring rats than that in resilience group. Administration of BMP4 inhibitor noggin to the pregnant rats suffering from restraint stress could result in an increase of the resilient offspring rats from 16.67% (5/30) to 56.67% (17/30). These observations indicate that BMP4 signaling may be a potential target for promoting resilience to depression for the offspring from maternal prenatal stress.

Alzheimeru2019s disease (AD) is a neurodegenerative disorder characterized by a gradual decline in cognitive abilities and memory loss. Recent studies have indicated that the microbiota-gut-brain axis (MGBA) may be involved in the development of this condition. This research aimed to clarify the composition and function of the MGBA, particularly focusing on the diversity of gut microbiota, and its connection to gut barrier integrity and the nervous system. Herein, we conducted a narrative review of existing literature to investigate how microbial metabolites affect neural function, neuroinflammation, and metabolic issues related to AD. The results of this study indicate that changes in the diversity of the gut microbiota can worsen neuroinflammation, thereby accelerating the progression of AD. Additionally, we discovered that neurotransmitters, which are influenced by the gut microbiota, play a regulatory role, pointing to potential targets for therapy. In exploring treatment options, we assessed the effectiveness of probiotics, dietary changes, and fecal microbiota transplantation (FMT) in managing AD. Clinical trials have demonstrated that specific probiotic strains can improve cognitive function, while dietary approaches, such as the Mediterranean diet, are associated with a reduced risk of developing AD. Moreover, FMT appears to be a promising new treatment strategy, although there are still challenges to its implementation. In summary, our research highlights the significant role of the MGBA in the pathogenesis and treatment of AD, suggesting that modifying gut microbiota could provide new opportunities for therapeutic intervention in AD.

Ischemic injury has been reported to induce mild to severe permanent deficits. Nevertheless, its recovery is often dynamic, depending on the plasticity of the injured neurons. The current study found that during the early stage of cerebral ischemia (1 h), Npas4 expression was increased in the hippocampus of mice, thereby transcriptionally regulated the expression of Neuroligin-1 and N-cadherin to enhance long-term potentiation. Knocking down of Npas4 reduced the level of Neuroligin-1 and N-cadherin, sequentially prevented the enhanced neural plasticity in the early cerebral ischemia. Furthermore, the downregulation of Neuroligin-1 and N-cadherin also impeded the ischemia-induced enhancement in neural plasticity without affecting the expression of Npas4. Overexpression of Npas4 in the primary neurons increased the number of VAMP2-labeled synaptic vesicles, while interfering the expression of Neuroligin-1 and N-cadherin in the primary neurons with siRNA reduced the increase of VAMP2-labeled synaptic vesicles without affecting the Npas4 expression. Interestingly, the transcriptional level of Npas4, Neuroligin-1, and N-cadherin declined in multiple brain regions of Alzheimer's disease (AD) patients and 3 × TG AD mice. Moreover, overexpression of Npas4 increased the expression of Neuroligin-1 and N-cadherin, ameliorated the synaptic plasticity impairment of 3 × TG mice, and enhanced the cognitive function. These findings suggest a previously undiscovered biological mechanism of neural plasticity, driven by Npas4 upregulation of Neuroligin-1 and N-cadherin, which partially explain why the compensatory increase in Npas4 in the early stages of ischemic injury and the lack of Npas4 in AD progression, highlighting potential therapeutic strategies for cognitive deficits.

Dysfunction of transactive response DNA-binding protein 43 (TDP-43) drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), in part through inducing aberrant RNA splicing. However, whether such mis-splicing yields stable, pathogenic proteins remains unclear. Here, we identify a TDP-43-repressed cryptic exon in Protein kinase N1 (PKN1), designated PKN1-5a1, which is activated in ALS patient brains and introduces a premature termination codon. This aberrant transcript escapes nonsense-mediated decay and is translated into a truncated peptide, PKN1-N207 (PKN207), detectable in AD brains with TDP-43 pathology. In mice, PKN207 impairs cognition, memory, and synaptic plasticity. Our findings demonstrate that TDP-43 loss-induced cryptic splicing can generate stable neurotoxic polypeptides, revealing a peptide-mediated mechanism in TDP-43 proteinopathies.

ABSTRACT Drug addiction is a debilitating condition that causes severe mental and physical impairments. Methamphetamine (METH) is one of the most commonly abused psychostimulants, mainly affecting the brain by releasing dopamine and serotonin. METH addiction has become a serious public health issue, and there is currently no specific treatment available. Although scientists have a good understanding of the mechanisms underlying drug addiction, including METH, our current biological and molecular knowledge of addiction is still incomplete. There is substantial evidence that addiction‐related changes are primarily mediated through gene expression regulation. Interestingly, the involvement of microRNAs (miRNAs) in this process could enhance our understanding of the molecular mechanisms underlying METH addiction. Therefore, further understanding the mechanisms behind METH‐induced differential changes in miRNAs, along with their pharmacological and genetic manipulation, could lead to promising new treatments for METH addiction. In this study, we first summarized epidemiological data and the addictive and neurotoxic mechanisms of METH, extensively reviewed studies on miRNA expression changes, discussed potential miRNA‐targeted therapeutic interventions for METH addiction, and outlined future research directions. We believe this study will provide a clearer understanding of the role of miRNAs in METH addiction and may help scientists develop more effective therapeutic strategies.

Interleukin-6 receptor (IL-6R) plays a pivotal role in Interleukin-6 (IL-6) signaling, which is an important pathogenic mechanism of cardiovascular and cerebrovascular diseases. IL-6R exists as membrane-bound and soluble forms and signals through classic, trans-, and cluster signaling that converge on JAK–STAT3, MAPK/ERK and PI3K–Akt pathways, while the IL-6 buffer system modulates signal intensity. Experimental studies show that IL-6 signaling drives acute-phase responses, dyslipidemia, endothelial activation, leukocyte recruitment, blood–brain barrier disruption, angiogenesis, and vascular remodeling. IL-6R is an important therapeutic target in inflammation, as evidenced by the approval of monoclonal antibodies like tocilizumab, sarilumab, and satralizumab. In addition, other emerging IL-6R-directed biologics and trans-signaling-selective approaches show promising anti-inflammatory activity in immune-mediated diseases. Mendelian randomization (MR) analyses using IL-6R variants as instruments indicate that partial lifelong downregulation of IL-6 signaling causally reduces the risk of coronary heart disease, ischemic stroke, abdominal aortic aneurysm, and other vascular phenotypes. Early clinical trials suggest tocilizumab has acceptable cardiovascular safety and improvements in acute inflammatory response, myocardial injury, and salvage. We propose that IL-6R might be a promising biomarker and therapeutic target for cardiovascular prevention and treatment. This review will summarize the role of IL-6R in cardiovascular and cerebrovascular diseases with reference to historical literature and discuss its potential clinical applications. Future studies should build large scale specific disease cohorts and further explore novel interventions targeting IL-6R signaling to advance the implementation of anti-inflammatory therapeutic strategies in this field.

Beta-hemoglobin (HBB) is expressed in neurons, though its function remains incompletely understood. Prenatal stress (PS) is a well-established risk factor for neuropsychiatric disorders; however, the molecular mechanisms underlying its long-term effects are still unclear. In this study, we demonstrated that PS induces persistent anxiety- and depression-like behaviors in adult rat offspring, along with a significant downregulation of HBB in prefrontal cortical neurons. Deficiency of HBB resulted in neuronal hypoxia, impairing dendritic development, synaptic function, and neuronal connectivity; whereas overexpression of HBB rescued these behavioral and neuronal deficits. In healthy control rat offspring, knockdown of HBB in prefrontal cortical neurons recapitulated the phenotypes induced by PS. To intervene in these pathogenic processes, we found that early-life hyperbaric oxygen therapy (HBOT) restored HBB expression, alleviated neuronal hypoxia, and prevented the development of affective disorders in adulthood. Our findings identify cortical HBB as a key mediator linking PS to neurodevelopmental impairments and suggest hyperbaric oxygen therapy as a potential therapeutic strategy for stress-related psychiatric disorders.

Background Clinically, phosphorylation of Tau protein at threonine 181 (p-Tau181) acts as a crucial biomarker for AD detection. However, the mechanisms through which Tau phosphorylation at threonine (Thr)181 site leads to Tau aggregation and corresponding neuropathological changes remain unclear. Objective To investigate the effect of the phosphorylated tau peptide at Thr181 on tau aggregation, synaptic and cognitive impairments. Methods We synthesized the phosphorylated tau peptide Tau-pT181 and the non-phosphorylated tau peptide Tau-nT181, and verified their effects on the aggregation of the Tau repeat domain R3 fragment peptide and Tau pathology. Results Thioflavin S assay showed that Tau-pT181 significantly promoted the aggregation of R3, whereas Tau-nT181 did not induce R3 aggregation. Moreover, Tau-pT181 not Tau-nT181 led to the aggregation of Tau protein in 293/tau cells and decreased synapse-associated proteins in primary hippocampal neurons. One month after injecting Tau-pT181 and Tau-nT181 respectively into the rat CA1 hippocampal region, we found that exclusively the phosphorylated peptide Tau-pT181 induced endogenous Tau aggregation, synaptic damage, neuronal loss, while Tau-pT181 group exhibited significant cognitive impairment compared with the normal saline rats. Transcriptome analysis of neurons differentiated from iPSCs treated with Tau-pT181/Tau-nT181 suggest that phosphorylated peptides had a greater impact on axonogenesis, neuronal development, and Wnt signaling pathway. Conclusions The present study offers the first direct evidence that Tau phosphorylation at Thr181 induces Tau aggregation, and Tau-pT181 directly leads to neuropathological alterations and cognitive impairments, and establishes a new theoretical foundation for Tau Thr181 phosphorylation site as a core diagnostic marker and therapeutic target for AD.

Circadian rhythm disorder (CRD) is a risk factor for cognitive deficits, yet its mechanisms remain unclear. We previously found CRD model mice developed cognitive impairment mediated through gut microbiota disturbance, intestinal barrier damage, and microglia activation, but the signaling pathway was undefined. Here, we show CRD induces cognitive deficits and gut microbiota disturbance in mice. Fecal microbiota transplantation (FMT) from CRD mice to normal mice reproduced intestinal barrier damage, microglia activation, neuronal damage, and cognitive deficits. Notably, gut metabolite analysis revealed significant alterations, with tryptophan metabolism being particularly affected: tryptophan decreased by 26.9 % and 5-hydroxytryptophan (5-HTP) by 30.7 % (both P < 0.05). Dietary tryptophan supplementation restored serum tryptophan and 5-HTP levels, ameliorating the neuronal damage and cognitive deficits caused by CRD gut microbiota. Collectively, these findings indicate that disturbances in gut microbiota and metabolites play a key role in CRD-induced neurological damage in mice, suggesting targeting the gut microbiota or tryptophan metabolism may prevent CRD-induced cognitive dysfunction.

The loss of astrocytes represents a key pathological hallmark of major depressive disorder, yet its mechanisms remain elusive. Here, we identified NDRG2 as a critical regulator of astrocyte apoptosis in depression. NDRG2 expression is upregulated in depression models, concomitant with astrocyte loss. Overexpression of NDRG2 in astrocytes triggered apoptosis and depressive-like behaviors, with inhibition of AKT and activation of FoxO3a-Puma apoptotic signaling pathway. Mechanistically, NDRG2 recruits PP2A to AKT, facilitating its dephosphorylation and subsequent inactivation, then promotes the nuclear translocation of FoxO3a, leading to the transcriptional activation of the pro-apoptotic factor Puma. Crucially, NDRG2 knockdown in astrocytes effectively prevented astrocytic apoptosis, with effective rescue of depressive-like phenotypes. These findings reveal a key mechanism of astrocyte death in depression, wherein NDRG2 functions as an adaptor to promote PP2A-mediated AKT dephosphorylation, thereby initiating the pro-apoptotic signaling pathway, and disclose a druggable pathway for developing antidepressants targeting astrocyte preservation.

Aging is the greatest risk factor for late-onset Alzheimer’s disease (LOAD), which accounts for > 95

Background p53 is a transcriptional factor that regulates numerous cellular processes, the stability and activity of p53 is essential to maintain its function. Post-translational modifications (PTMs), particularly SUMOylation, play a vital role in regulating p53 activity. Objective To investigate the neurogenesis related genes that downregulated by p53 SUMOylation in APP/PS1 mice, and the protected effect by overexpressing non-SUMOylated p53 (p53 K386R). Furthermore, to provide new clues for the mechanisms of Alzheimer's disease (AD). Methods Co-immunoprecipitation was used to detect the p53 SUMOylation levels in neuro2a (N2a) cells and APP/PS1 mice overexpressing wild-type p53 (p53 WT) or p53 K386R. In addition, RNA sequencing (RNA-seq) was used to detect the p53 SUMOylation regulated genes. Then we used qPCR, western blot, and immunofluorescence to measure the expression of neuroglobin (ngb) and the effect of neurogenesis defects induced by p53 SUMOylation. Results We verified that overexpression of p53 WT promoted p53 SUMOylation and p53 K386R decreased p53 SUMOylation in N2a cells and APP/PS1 mice. Ngb was related to neurogenesis which dramatically downregulated by p53 SUMOylation. In addition, we found p53 SUMOylation caused neuron reduction and impairment of neurogenesis. Conclusions Our data support that p53 SUMOylation may lead to neurogenesis defects by downregulating ngb in AD, suggesting that inhibition of p53 SUMOylation may be served as a therapeutic strategy for preventing AD and provide a new target for future researches and interventions.

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.

This study identifies a novel function of Sortilin-related receptor with A-type repeats (SORLA), traditionally linked to Alzheimer's Disease (AD) as a high-risk gene and associated with neuronal function, in modulating microglial responses to ischemic stroke. We discovered that SORLA expression is significantly reduced in microglia following stroke, a change linked to increased brain injury and diminished neurological recovery. Utilizing SORLA knockout and overexpression models, we demonstrated its essential role in adjusting microglial inflammatory responses. Notably, microglial-specific overexpression of SORLA not only promoted anti-inflammatory actions and effective phagocytosis but also surpassed traditional concepts of microglial polarization. This overexpression mitigated brain damage and enhanced neurofunctional recovery post-stroke, highlighting the neuroprotective potential of SORLA. This breakthrough challenges the prevailing understanding the role of SORLA and opens new therapeutic possibilities for stroke recovery, indicating its wider relevance for neurodegenerative disease management.

Aging is a major risk factor for Alzheimer’s disease (AD). With the prevalence of AD increased, a mechanistic linkage between aging and the pathogenesis of AD needs to be further addressed. Here, we report that a small ubiquitin-related modifier (SUMO) modification of p53 is implicated in the process which remarkably increased in AD patient’s brain. Mechanistically, SUMOylation of p53 at K386 residue causes the dissociation of SET/p53 complex, thus releasing SET into the cytoplasm, SET further interacts with cytoplasmic PP2A and inhibits its activity, resulting in tau hyperphosphorylation in neurons. In addition, SUMOylation of p53 promotes the p53 Ser15 phosphorylation that mediates neuronal senescence. Notably, p53 SUMOylation contributes to synaptic damage and cognitive defects in AD model mice. We also demonstrate that the SUMOylation inhibiter, Ginkgolic acid, recovering several senescent phenotypes drove by p53 SUMOylation in primary neurons. These findings suggest a previously undiscovered etiopathogenic relationship between aging and AD that is linked to p53 SUMOylation and the potential of SUMOylated p53-based therapeutics for neurodegeneration such as Alzheimer’s disease.

Circadian rhythm disruption (CRD) is a potential risk factor for the development of depression. However, the underlying mechanisms remain unclarified. Here, it is found that in CRD model mice showing significant depressive-like behaviors, the expression rhythm of Period 2 (Per2), an important rhythm gene, is disrupted in intestinal epithelium, which results in defect of gut barrier integrity and gut microbiota disturbance, accompanied by peripheral and neuroinflammation, deficit in hippocampal neurogenesis, and impairment of excitatory neurotransmission. Specific knockdown of Per2 gene in intestinal epithelial cells prevents the development of depression-like phenotype induced by CRD, with a reverse of these pathologic changes. Metabonomic analysis reveals that both CRD and CRD gut microbiota-transplanted mice have downregulated tryptophan metabolism and reduced tryptophan levels both in serum and brain, and tryptophan supplementation is sufficient to prevent CRD-induced depression, reduce systemic and neuronal inflammatory response, and rescue neurogenesis and synaptic function. These data suggest that the disturbed expression of intestinal epithelial Per2 gene plays a critical role in CRD-induced neurological damage and depression in mice, which is mediated by gut microbiota and metabolites. Therefore, specific targeting on intestinal epithelial Per2 or tryptophan metabolism is a promising strategy to prevent CRD-induced depression.

High-salt (HS) diet is an established risk factor for cognitive impairment, but the underlying mechanisms remain unclear. This study reveals that HS diet reduces SHANK1, a key postsynaptic scaffolding protein, via downregulation of the PKA/CREB pathway, leading to synaptic dysfunction and cognitive deficits in rats. RNA sequencing of HS-fed rat hippocampi showed downregulation of cAMP signaling and SHANK1 expression. Pharmacological inhibition of PKA/CREB reduced SHANK1 levels and impaired dendritic structure and synaptic function, while PKA activation restored CREB activity and SHANK1 expression, reversing HS-induced deficits. Notably, CREB activation is essential for SHANK1 regulation, as a CREB mutant (S133A) blocked the effects of PKA activation, and a constitutively active CREB (S133D) prevented SHANK1 downregulation. These findings highlight the PKA/CREB/SHANK1 pathway as a potential therapeutic target for HS-induced cognitive dysfunction.

Cytoplasmic aggregation of transactive response DNA-binding protein 43 (TDP-43) is a hallmark of amyotrophic lateral sclerosis (ALS) and occurs in 57% of Alzheimer's disease (AD) cases. TDP-43 regulates RNA processing, including cryptic exon splicing. Here, we demonstrate that TDP-43 directly controls growth-associated protein (GAP43) expression by binding to its pre-mRNA. Loss or hyperphosphorylation of TDP-43 disrupts this binding, leading to the inclusion of cryptic exon 4a1, which introduces premature stop codons and reduces GAP43 protein levels. RNA sequencing analysis of ALS and AD brains revealed GAP43 downregulation, while 4a1 is upregulated in AD cases with phosphorylated TDP-43. TDP-43 knockdown impaired axonal regeneration in induced pluripotent stem cell (iPSC)-derived motor neurons, whereas GAP43 restoration rescued this defect. These findings suggest that the loss of GAP43 contributes to neurodegeneration in ALS and AD. The inclusion of GAP43 cryptic exon 4a1 may serve as a hallmark of TDP-43 proteinopathies, highlighting a mechanistic link between TDP-43 dysfunction and neuronal vulnerability.