Ischemic stroke (IS) represents a significant global health burden with increasing incidence, creating an urgent need for novel therapeutic approaches. This study explored the neuroprotective effects of nicotinamide adenine dinucleotide phosphate (NADPH) in preserving blood-brain barrier (BBB) integrity and promoting angiogenesis after IS. Through network pharmacology analysis and molecular docking, five key molecular targets of NADPH in IS were identified: HIF-1α, SRC, NLRP3, CASP3, and AKT1. In vivo, NADPH treatment conferred significant protection against cerebral ischemia in the transient middle cerebral artery occlusion (tMCAO) model. At the optimal dose of 7.5 mg/kg, it substantially reduced infarct volume (∼50%), attenuated cerebral edema (from 81% to 76%), improved neurological function (∼58%), and preserved BBB integrity. Mechanistically, NADPH protected the BBB by upregulating key tight junction (TJ) proteins, including a ∼29% increase in ZO-1 expression, with electron microscopy confirming strengthened TJ structure. NADPH also reduced the protein levels of matrix metalloproteinase-9 (MMP9) and caveolin-1 by ∼23% and 50%, respectively. Furthermore, it suppressed NLRP3 inflammasome activation, decreased the expression of NLRP3 (∼14%), ASC (∼24%), Caspase-1 (∼30%), and interleukin-1β (IL-1β; ∼16%), thereby attenuating inflammation. In vitro, NADPH enhanced endothelial cell proliferation, migration, and tube formation under oxygen-glucose deprivation (OGD) conditions. Additionally, NADPH further elevated the expression of key pro-angiogenic markers, increasing HIF-1α protein by ∼77.1% and vascular endothelial growth factor (VEGF) by ∼44.8% at day 7 post-tMCAO. These findings suggest that NADPH confers neuroprotection in IS by preserving BBB integrity, inhibiting NLRP3 inflammasome-mediated damage, and stimulating angiogenesis through HIF-1α/VEGF signaling. Our results highlight NADPH's dual therapeutic mechanisms and its potential as a promising neuroprotective agent for IS.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline accompanied by chronic neuroinflammation. Emerging evidence implicates T-cell infiltration and microglial activation as key immune events that accelerate AD pathology, yet therapeutic approaches targeting this neuroimmune interface remain scarce. Cobrotoxin (CTX), a short-chain neurotoxin derived from Naja atra venom, exhibits potent anti-inflammatory and immunomodulatory properties and is clinically approved in China for the treatment of chronic pain syndromes. Here, we investigated whether CTX could alleviate neuroinflammation and cognitive deficits in 5 × FAD mice, a transgenic model of AD. Intranasal CTX administration for nine weeks enhanced spatial learning and memory in the Morris water maze without altering amyloid-β burden. Flow cytometry and immunofluorescence revealed that CTX markedly reduced brain-infiltrating CD8+ T cells and downregulated chemokines implicated in T cell-microglia communication, including Cxcl9, Cxcl10, Cxcl16, and Ccl5. Consistent with this, CTX attenuated microglial activation and pro-inflammatory cytokine release while preserving plaque-associated microglia (disease-associated microglia, DAM). Morphological and electrophysiological analyses demonstrated that CTX restored dendritic complexity, spine density, and hippocampal long-term potentiation (LTP), indicating improved synaptic integrity. Collectively, these findings identify CTX as a potent modulator of neuroimmune signaling that mitigates neuroinflammation and synaptic dysfunction in AD, suggesting its potential for repurposing as an immunomodulatory therapy for neurodegenerative diseases.

Alzheimer's disease (AD) is a gradually worsening neurodegenerative condition marked by the accumulation of amyloid-β plaques and a decline in cognitive abilities. Emerging research emphasizes astrocytic metabolic disturbances as contributors to AD development. This study investigates the therapeutic effects of Verapamil (VPM), a clinically approved calcium channel blocker, on astrocytic glycolysis in 3 × Tg-AD mice, focusing on the involvement of the thioredoxin-interacting protein (TXNIP)/glucose transporter 1 (GLUT1) pathway. VPM treatment significantly enhanced glycolytic activity in astrocytes, as evidenced by increased lactate production and improved metabolic function. Western blot and PCR analyses revealed a reduction in TXNIP levels and an upregulation of GLUT1 expression, particularly in the plasma membrane fraction, suggesting enhanced glucose uptake and glycolysis. Additionally, VPM treatment decreased soluble β-amyloid (Aβ) levels and alleviated cognitive impairments in the 3 × Tg-AD mice. These findings indicate that VPM restores glycolytic function in astrocytes through the TXNIP/GLUT1 pathway, offering a promising intervention targeting metabolic disruption and cognitive decline in AD. This study underscores the critical role of glycolysis in glial cells and highlights VPM's therapeutic potential in AD by targeting metabolic dysfunction.

Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-β (Aβ) deposition, synaptic dysfunction, and progressive cognitive decline. Emerging evidence suggests that peripheral inflammation, particularly intestinal inflammation, can aggravate AD pathology through the gut-brain axis. As key mediators of intestinal inflammation and systemic immune activation, neutrophils have emerged as critical contributors to AD progression. In this study, we investigated how dextran sulfate sodium (DSS)-induced colitis influences Aβ pathology and synaptic integrity in 5 × FAD mice, focusing on the role of neutrophil glycolysis and neutrophil elastase (NE) activation. DSS-induced colitis significantly exacerbated AD-like pathology, as evidenced by pronounced body-weight loss, colon shortening, increased brain neutrophil infiltration, and elevated NE expression in the hippocampus, accompanied by enhanced Aβ plaque burden and reduced dendritic spine density. These findings indicate that DSS-triggered peripheral inflammation promotes central immune activation and accelerates Aβ pathology via metabolic reprogramming of neutrophils. Administration of the glycolytic inhibitor PFK-158 effectively suppressed NE expression and mitigated Aβ accumulation. Peripheral injection of PFK-158 attenuated neuroinflammation and partially restored dendritic structure, while intracerebroventricular infusion directly inhibited central neutrophil activation and improved hippocampal synaptic transmission, as reflected by enhanced field excitatory postsynaptic potentials (fEPSPs) and long-term potentiation (LTP). Collectively, these results demonstrate that DSS-induced colitis aggravates AD pathology by enhancing neutrophil glycolysis and NE release, linking peripheral metabolic inflammation to central neurodegeneration. Targeting neutrophil glycolytic activation with PFK-158 represents a promising therapeutic strategy to disrupt gut-brain inflammatory crosstalk and slow AD progression.

Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid plaques and neuroinflammation, which collectively result in cognitive decline. Peripheral inflammation, particularly intestinal inflammation, has been implicated in exacerbating AD pathology via the gut-brain axis. This study investigated the effects of dextran sulfate sodium (DSS)-induced colitis on amyloid-beta (Aβ) pathology, synaptic integrity, and cognitive function in 5xFAD mice, and explored the roles of neutrophil elastase (NE) and Cathepsin B in these processes. DSS-induced colitis significantly worsened Aβ pathology, evidenced by increased Aβ plaque deposition and elevated soluble Aβ1-42 levels in the brain of 5xFAD mice. The inflammatory state triggered extensive neutrophil infiltration and elevated NE levels in the hippocampus, which were closely associated with Cathepsin B activation. This enzymatic cascade is associated with synaptic damage and cognitive deficits. Treatment with the NE inhibitor Sivelestat effectively suppressed NE-mediated Cathepsin B activation, reduced Aβ pathology, restored dendritic spine density, and improved cognitive performance. Additionally, the Cathepsin B inhibitor CA-074 methyl ester (CA-074Me) mitigated the adverse effects of DSS-induced colitis, further emphasizing the role of Cathepsin B in mediating inflammation-driven AD pathology. These findings reveal that the NE-Cathepsin B axis links peripheral inflammation to exacerbated Aβ pathology, synaptic damage, and cognitive impairment, underscoring the potential of targeting NE and Cathepsin B as therapeutic strategies for inflammation-driven AD progression.

Gangliosides serve as receptors for proteins, bacteria, and viruses, with sialylation at the termini of their glycan chains playing a crucial role in ligand recognition and endocytosis. The internalization of proteopathic tau aggregates by neurons is integral to the propagation of tau pathology in Alzheimer’s disease (AD). However, the influence of gangliosides and their sialylation modifications on the uptake of proteopathic tau aggregates and the subsequent impact on AD pathology remains unclear. This study investigates the roles of the four mammalian sialidases (Neu1-Neu4) in modulating tau aggregation in cellular models. Our findings demonstrate that Neu3 significantly inhibits tau aggregation induced by proteopathic tau derived from the brains of AD patients (AD P-tau). Overexpressing Neu3 or administering ganglioside GM1, which results from Neu3-catalyzed removal of one sialic acid from GD1a, in the mouse model decreases the GD1a/GM1 ratio in mouse brain, effectively blocks the spread of tau pathology and improves recognition in AD P-tau-injected mice. Both Neu3 and GM1 reduce the internalization of tau aggregates, while GD1a enhances tau uptake, showing a positive correlation with the level of internalized tau. Moreover, the internalization of tau mediated by GD1a dependent on low-density lipoprotein receptor-related protein 1 (LRP1) and compensates for heparin-inhibited tau uptake. In vitro assays demonstrate that GD1a exhibits a higher binding avidity for tau filaments than GM1. These findings indicate that GD1a may directly bind to tau aggregates via the sialic acid moiety, facilitating LRP1-mediated tau uptake. This study proposes a novel mechanism for tau internalization and posits that reducing ganglioside sialylation may be a promising strategy for hindering the spread of tau pathology in AD.

Background Endoplasmic reticulum stress plays a crucial role in the pathogenesis of neuroinflammation and chronic pain. This study hypothesized that PRKR-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme type 1 (IRE1) regulate lipocalin-2 (LCN2) and Nod-like receptor family pyrin domain containing 3 (NLRP3) expression in astrocytes, thereby contributing to morphine tolerance and hyperalgesia. Methods The study was performed in Sprague–Dawley rats and C57/Bl6 mice of both sexes. The expression of LCN2 and NLRP3 was assessed by Western blotting. The tail-flick, von Frey, and Hargreaves tests were used to evaluate nociceptive behaviors. Chromatin immunoprecipitation was conducted to analyze the binding of activating transcription factor 4 (ATF4) to the promoters of LCN2 and TXNIP. Whole-cell patch-clamp recordings were used to evaluate neuronal excitability. Results Pharmacologic inhibition of PERK and IRE1 attenuated the development of morphine tolerance and hyperalgesia in male (tail latency on day 7, 8.0 ± 1.13 s in the morphine + GSK2656157 [10 μg] group vs. 5.8 ± 0.65 s in the morphine group; P = 0.04; n = 6 rats/group) and female (tail latency on day 7, 6.0 ± 0.84 s in the morphine + GSK2656157 [10 μg] group vs. 3.1 ± 1.09 s in the morphine group; P = 0.0005; n = 6 rats/group) rats. Activation of PERK and IRE1 upregulated expression of LCN2 and NLRP3 in vivo and in vitro. Chromatin immunoprecipitation analysis showed that ATF4 directly bound to the promoters of the LCN2 and TXNIP. Lipocalin-2 induced neuronal hyperexcitability in the spinal cord and dorsal root ganglia via melanocortin-4 receptor. Conclusions Astrocyte endoplasmic reticulum stress sensors PERK and IRE1 facilitated morphine tolerance and hyperalgesia through upregulation of LCN2 and NLRP3 in the spinal cord. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Methyl-CpG-binding protein 2 (Mecp2) is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little attention has been given to its potential contributions to the peripheral nervous system (PNS). To investigate the regulation of Mecp2 in the PNS on specific central regions, we generated Mecp2fl/flAdvillincre mice with the sensory-neuron-specific deletion of the Mecp2 gene and found the mutant mice had a heightened sensitivity to temperature, which, however, did not affect the sense of motion, social behaviors, and anxiety-like behavior. Notably, in comparison to Mecp2fl/fl mice, Mecp2fl/flAdvillincre mice exhibited improved learning and memory abilities. The levels of hippocampal synaptophysin and PSD95 proteins were higher in Mecp2fl/flAdvillincre mice than in Mecp2fl/fl mice. Golgi staining revealed a significant increase in total spine density, and dendritic arborization in the hippocampal pyramidal neurons of Mecp2fl/flAdvillincre mice compared to Mecp2fl/fl mice. In addition, the activation of the BDNF-TrkB-CREB1 pathway was observed in the hippocampus and spinal cord of Mecp2fl/flAdvillincre mice. Intriguingly, the hippocampal BDNF/CREB1 signaling pathway in mutant mice was initiated within 5 days after birth. Our findings suggest a potential therapeutic strategy targeting the BDNF-TrkB-CREB1 signaling pathway and peripheral somasensory neurons to treat learning and cognitive deficits associated with Mecp2 disorders.

Extracellular amyloid plaques made of Amyloid-β (Aβ) derived from amyloid precursor protein (APP) is one of the major neuropathological hallmarks of Alzheimer’s disease (AD). There are three major isoforms of APP, APP770, APP751, and APP695 generated by alternative splicing of exons 7 and 8. Exon 7 encodes the Kunitz protease inhibitor (KPI) domain. Its inclusion generates APP isoforms containing KPI, APPKPI+, which is elevated in AD and Down syndrome (DS) brains and associated with increased Aβ deposition. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) phosphorylates many splicing factors and regulates the alternative splicing of pre-mRNA. It is upregulated in DS and AD brain. However, it is not yet clear whether Dyrk1A could regulate APP alternative splicing. In the present study, we overexpressed or knocked down Dyrk1A in cultured cells and observed that Dyrk1A promoted the inclusion of both APP exons 7 and 8. Moreover, a significant increase in APP exon7 inclusion was also detected in the forebrain and hippocampus of human Dyrk1A transgenic mice – Tg/Dyrk1A. Screening for splicing factors regulated by Dyrk1A revealed that serine/arginine-rich protein 9G8 inhibited APP exon7 inclusion and interacted with APP pre-mRNA. In vitro, expression of exon 7 facilitated APP cleavage. In human Dyrk1A transgenic mice, we also found an increase in Aβ production. These findings suggest that Dyrk1A inhibits the splicing factor 9G8 and promotes APP exon 7 inclusion, leading to more APPKPI+ expression and APP cleavage and potentially contributing to Aβ production in vivo.

Brain consumes nearly 20% supply of energy from glucose metabolism by oxidative phosphorylation and aerobic glycolysis. Less active state of glycolytic enzymes results in a limited capacity of glycolysis in the neurons of adult brain. Here we identified that Warburg effect is enhanced in hippocampal neurons during aging. As hippocampal neurons age, lactate levels progressively increase. Notably, we observed upregulated protein levels of PFKFB3 in the hippocampus of 20-month-old mice compared to young mice, and this higher PFKFB3 expression correlated with declining memory performance in aging mice. Remarkably, in aging mice, knocking down Pfkfb3 in hippocampal neurons rescued cognitive decline and synapse loss. Conversely, Pfkfb3 overexpression in hippocampal neurons led to cognitive impairment and synapse elimination, associated with heightened glycolysis. In vitro experiments with cultured primary neurons confirmed that Pfkfb3 overexpression increased glycolysis and that glycolytic inhibition could prevent apoptotic competency in neurons. These findings underscore that glycolysis in hippocampal neurons could potentially be targeted as a therapeutic avenue to mitigate cognitive decline and preserve synaptic integrity during aging.

Alzheimer's disease is characterized by two major neuropathological hallmarks-the extracellular β-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein. Recent studies suggest that dysregulation of the microtubule-associated protein Tau, especially specific proteolysis, could be a driving force for Alzheimer's disease neurodegeneration. Tau physiologically promotes the assembly and stabilization of microtubules, whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers, resulting in them gaining prion-like characteristics. In addition, Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner. This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments, investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease, and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.

Melatonin confers protection against myocardial injury by reducing inflammation and inhibiting apoptosis. In the present study, we investigated whether melatonin regulates cardiomyocyte proliferation and improves cardiac function in rats with myocardial infarction (MI). Two MI models were established in vitro (H9c2 cells were cultured under hypoxia) and in vivo (the left anterior descending coronary artery of rats was surgically ligated). miR-200b-3p and high mobility group box 1 (HMGB1) levels were detected. Cell proliferation and apoptosis were analyzed in vitro, and cardiac function, inflammatory cytokines, and myocardial injury markers in vivo were tested. The experimental results reported that melatonin promoted proliferation and impaired apoptosis of H9c2 cells cultured in hypoxia. In vivo, melatonin improved cardiac function and inhibited the inflammation and myocardial injury of rats with MI. miR-200b-3p was downregulated and HMGB1 was upregulated in MI, while melatonin could upregulate miR-200b-3p and downregulate HMGB1. The HMGB1 was targeted by miR-200b-3p. Upregulating miR-200b-3p or downregulating HMGB1 could further promote the therapeutic effect of melatonin, and downregulating miR-200b-3p or upregulating HMGB1 could abolish the therapeutic effect of melatonin. In conclusion, melatonin alleviates inflammation and cardiac dysfunction after MI by regulating the miR-200b-3p/HMGB1 axis, offering a new therapeutic strategy for MI.

Use of folic acid (FA) during early pregnancy protects against birth defects. However, excess FA has shown gender-specific neurodevelopmental toxicity. Previously, we fed the mice with 2.5 times the recommended amount of FA one week prior to mating and during the pregnancy and lactation periods, and detected the activated expression of Fos and related genes in the brains of weaning male offspring, as well as behavioral abnormalities in the adults. Here, we studied whether female offspring were affected by the same dosage of FA. An open field test, three-chamber social approach and social novelty test, an elevated plus-maze, rotarod test and the Morris water maze task were used to evaluate their behaviors. RNA sequencing was performed to identify differentially expressed genes in the brains. Quantitative real time-PCR (qRT-PCR) and Western blots were applied to verify the changes in gene expression. We found increased anxiety and impaired exploratory behavior, motor coordination and spatial memory in FA-exposed females. The brain transcriptome revealed 36 up-regulated and 79 down-regulated genes in their brains at weaning. The increase of Tlr1; Sult1a1; Tph2; Acacb; Etnppl; Angptl4 and Apold1, as well as a decrease of Ppara mRNA were confirmed by qRT-PCR. Among these genes; the mRNA levels of Etnppl; Angptl4andApold1 were increased in the both FA-exposed female and male brains. The elevation of Sult1a1 protein was confirmed by Western blots. Our data suggest that excess FA alteres brain gene expression and behaviors in female offspring, of which certain genes show apparent gender specificity.

The progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) correlates with rupture of lysosome in Parkinson's disease (PD). It has been found that TP53-induced glycolysis and apoptosis regulator (TIGAR) has been attributed to the regulation of metabolic pathways and neuroprotective effect. In the present study, we showed in a mouse model that 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) caused lysosomal damage and DA neurons loss in the SNpc. MPTP only induced SP1-mediated TIGAR upregulation in the early stage of neurotoxin-induced pathology, and this compensatory mechanism was not enough to maintain normal lysosomal function. MPTP significantly decreased the levels of NADPH and GSH, and the effects were ameliorated by the expression of exogenous TIGAR but execerbated by knockdown of TIAGR. TIGAR or NADPH alleviated oxidative stress, rescued lysosomal dysfunction and attenuated DA neurons degeneration. Overexpression of TIGAR or NADPH supplement inhibited MPP+-mediated reactive oxygen species (ROS), lysosomal membrane permeabilization (LMP) and autophagic flux impairment in PC12 cells. Together, these findings suggest that TIGAR reduces MPTP-mediated oxidative stress, lysosomal depletion and DA neuron damage.

Mild cognitive impairment in Parkinson's disease (PD-MCI) is considered as a nonmotor clinical symptom in Parkinson's disease (PD). Microglia-mediated inflammation contributes to cognitive function impairment. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurons degeneration in PD. But whether P188 could ameliorate cognitive impairment in PD is still illusive. In the present study, we showed in a mouse model that paraquat (10 mg/kg) and maneb (30 mg/kg) (P + M) treatment intraperitoneally twice a week for 6 consecutive weeks resulted in cognitive deficits and synapse loss in hippocampus, together with DA neuron damage in the substantia nigra pars compacta (SNpc). P188 (0.8 g/kg) injection via tail vein 30 min after P + M administration significantly restored DA neuron numbers in SNpc and synapse density in hippocampus, and alleviated P + M-mediated cognitive function impairment in novel object recognition task and morris water maze task (MWM). Pathological synapse loss might be attributed to increased microglial phagocytic activity and cell density, and P188 prevented P + M-induced phagocytic state changes of microglia, such as increase in cell body size and decrease in process length, and upregulated microglia abundance in hippocampus. Consistently, P188 attenuated P + M-mediated increased mRNA levels of microglia proliferation related CSF1r and CSF2ra, microglial engulfment associated CD68, ICAM1, and ICAM2, and pro-inflammatory IL-6, IL-1β, CD11b, and TNF-α in hippocampus. Together, these findings suggest that the biocompatible polymer P188 blunts microglia activation which may promote synaptic loss and exacerbate cognitive function in a mouse model of PD-MCI.

Repetitive traumatic brain injury (TBI) has been linked to late life development of chronic traumatic encephalopathy (CTE), a neurodegenerative disorder histopathologically characterized by perivascular tangles of hyperphosphorylated tau at the depth of sulci to later widespread neurofibrillary pathology. Although tau hyperphosphorylation and neurofibrillary-like pathology have been observed in the brain of transgenic mice overexpressing human tau with aggregation-prone mutation after TBI, they have not been consistently recapitulated in rodents expressing wild-type tau only. Here, we characterized Alzheimer-like alterations behaviorally, biochemically and immunohistochemically 6 weeks and 7 months after unilateral mild-to-moderate controlled cortical impact (CCI) in 5-7-month-old Tg/htau mice, which express all six isoforms of non-mutated human tau in a mouse tau null background. We detected hyperphosphorylation of tau at multiple sites in ipsilateral hippocampus 6 weeks but not 7 months after CCI. However, neuronal accumulation of AT8 positive phospho-tau was sustained in the chronic phase, in parallel to prolonged astrogliosis, and decreased neural and synaptic markers. The mice with CCI also exhibited cognitive and locomotor impairment. These results indicate subacute to chronic Alzheimer-like alterations after CCI in Tg/htau mice. This is the first known study providing insight into the role of CCI in Alzheimer-like brain alterations in young adult mice expressing only non-mutated human tau.

Background and PurposeDeveloping novel pharmacological targets beyond the monoaminergic system is now a popular strategy for treating depression. PPARα is a nuclear receptor protein that functions as a transcription factor,‐regulating gene expression. We have previously reported that both WY14643 and fenofibrate, two pharmacological agonists of PPARα, have antidepressant‐like effects in mice, implying that PPARα is a potential antidepressant target.Experimental ApproachWe first used various biotechnological methods to evaluate the effects of chronic stress and fluoxetine on hippocampal PPARα. The viral‐mediated genetic approach was then employed to explore whether hippocampal PPARα was an antidepressant target. PPARα inhibitors, PPARα‐knockout (KO) mice and PPARα‐knockdown (KD) mice were further used to determine the role of PPARα in the antidepressant effects of fluoxetine.Key ResultsChronic stress significantly decreased mRNA and protein levels of PPARα in the hippocampus, but not other regions, and also fully reduced the recruitment of hippocampal PPARα to the cAMP response element‐binding (CREB) promoter. Genetic overexpression of hippocampal PPARα induced significant antidepressant‐like actions in mice by promoting CREB‐mediated biosynthesis of brain‐derived neurotrophic factor. Moreover, fluoxetine notably restored the stress‐induced negative effects on hippocampal PPARα. Using PPARα antagonists fully blocked the antidepressant effects of fluoxetine in mice, and similarly, both PPARα‐KO and PPARα‐KD abolished the effects of fluoxetine. Besides, PPARα‐KO and PPARα‐KD aggravated depression in mice.Conclusions and ImplicationsHippocampal PPARα is a potential novel antidepressant target that mediates the antidepressant actions of fluoxetine in mice.

In the brains of individuals with Alzheimer's disease (AD) and chronic traumatic encephalopathy, tau pathology is accompanied usually by intracellular aggregation of transactive response DNA-binding protein 43 (TDP-43). However, the role of TDP-43 in tau pathogenesis is not understood. Here, we investigated the role of TDP-43 in tau expression in vitro and in vivo. We found that TDP-43 suppressed tau expression by promoting its mRNA instability through the UG repeats of its 3΄-untranslated region (3΄-UTR). The C-terminal region of TDP-43 was required for this function. Neurodegenerative diseases-causing TDP-43 mutations affected tau mRNA instability differentially, in that some promoted and others did not significantly affect tau mRNA instability. The expression levels of tau and TDP-43 were inverse in the frontal cortex and the cerebellum. Accompanied with cytoplasmic accumulation of TDP-43, tau expression was elevated in TDP-43M337V transgenic mouse brains. The level of TDP-43, which is decreased in AD brains, was found to correlate negatively with the tau level in human brain. Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. Down-regulation of TDP-43 may be involved in the tau pathology in AD and related neurodegenerative disorders.