Neurochem. Int. [JOURNAL]
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200 papers
Degradation of alpha-synuclein/SNCA mRNA by RNautophagy.
Kabuta C, Hakuno F, Kataoka N … +2 more , Takahashi SI, Kabuta T
Neurochem Int · 2026 May · PMID 41747943 · Publisher ↗
α-Synuclein is a neuronal protein and main component of Lewy bodies, the pathological hallmark of Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies. While the accumulation of α-synuclein in neu...
α-Synuclein is a neuronal protein and main component of Lewy bodies, the pathological hallmark of Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies. While the accumulation of α-synuclein in neurons is implicated in the pathogenesis of these disorders, the mechanisms underlying α-synuclein mRNA degradation remain poorly understood. RNautophagy is a lysosomal RNA degradation pathway in which RNA is directly taken up into lysosomes and subsequently degraded. SIDT2, a lysosomal membrane protein, mediates the uptake of RNA. In this study, we investigated whether SIDT2-mediated RNautophagy degrades α-synuclein mRNA. Knockdown of SIDT2 led to reduced degradation of α-synuclein mRNA, whereas overexpression of wild-type SIDT2 enhanced its degradation, suggesting its role in α-synuclein mRNA turnover. In contrast, overexpression of the RNA uptake-deficient S564A mutant did not enhance degradation, indicating that RNA uptake activity is required for SIDT2-mediated degradation of α-synuclein mRNA. Using a series of deletion mutants, we identified a guanine (G)-rich sequence within the 5' untranslated region (5'-UTR) of α-synuclein mRNA as a key determinant of SIDT2-dependent degradation. Furthermore, insertion of the G-rich sequence into the 5'-UTR of GFP mRNA promoted SIDT2-dependent degradation of GFP mRNA and reduced GFP protein expression. Taken together, these results indicate that SIDT2-mediated RNautophagy contributes to the degradation of α-synuclein mRNA via the G-rich region within the 5'-UTR. Our findings may also provide insights into the pathogenesis of Lewy body diseases.
Comparative neurochemical and neuroprotective effects of lauric acid, ribose-cysteine, and levodopa in an α-synuclein Drosophila model of Parkinson's disease.
Idowu OK, Oremosu AA, Dosumu OO
Neurochem Int · 2026 · PMID 41740678 · Publisher ↗
Parkinson's disease (PD) entails dopaminergic neuronal loss in a gradual manner, which is typically linked to oxidative stress, neuroinflammation, and the neurotransmitter homeostasis disruption. This research compares t...
Parkinson's disease (PD) entails dopaminergic neuronal loss in a gradual manner, which is typically linked to oxidative stress, neuroinflammation, and the neurotransmitter homeostasis disruption. This research compares the neurochemical and neuroprotective impacts of lauric acid (LA), ribose-cysteine (RC), and levodopa (LD) in a transgenic Drosophila melanogaster model where human α-synuclein (α-syn) was expressed in dopaminergic neurons. The transgenic flies received treatment with LA, RC, or LD (250 mg/kg diet) for three weeks and were then evaluated by behavioral assays in conjunction with biochemical and molecular analyses of redox status, inflammatory and apoptotic signaling, neurotransmitter levels, and dopaminergic gene expression. Expression of α-syn caused significant deficiencies of locomotor behavior, oxidative damage, activation of neuroinflammation, changes of dopamine, GABA, and glutamate levels, and reduction of dopa decarboxylase expression. All interventions led to substantial increments in behavioral outcomes and oxidative stress status when compared to untreated PD flies. Out of the three treatments, the RC-induced effects on total antioxidant capacity and cell viability were most notable, along with reduction of lipid peroxidation, TNF-α, and caspase-3 activity. LD was the best at restoring locomotor performance and dopamine levels, whereas LA and RC were more potent at apoptotic signaling reduction and dopaminergic gene expression enhancement. Overall, RC effected broader neurochemical modulation than LA across most parameters. The results from this study suggest that LA, RC, and LD have different yet complementary neuroprotective effects in α-syn-induced neurotoxicity and that RC is particularly effective in modulating oxidative and inflammatory pathways that are involved in PD pathophysiology.
Retinoic acid signaling regulates astrocyte reactivity by modulating MAPK/NF-κB pathways and mitochondrial integrity.
Yoo SH, Kim D, Yeon GB … +5 more , Choi J, Lee J, Kim DW, Kim H, Kim DS
Neurochem Int · 2026 · PMID 41724387 · Publisher ↗
Astrocytes respond to inflammatory stimuli by adopting a reactive state characterized by morphological, molecular, and functional changes that affect tissue repair and disease progression. A key feature of this transform...
Astrocytes respond to inflammatory stimuli by adopting a reactive state characterized by morphological, molecular, and functional changes that affect tissue repair and disease progression. A key feature of this transformation is the metabolic shift that supports inflammatory signaling and cytokine production. Retinoic acid (RA) modulates immune responses in the peripheral system; however, its role in astrocyte reactivity remains poorly understood. In this study, we investigated alterations in RA metabolism using an in vitro model of reactive astrocytes derived from human pluripotent stem cells. Reactivity was induced by treatment with tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), collectively referred to as TIC, and characterized using comprehensive morphological, molecular and functional analyses. We found that the induced reactive astrocytes exhibited a marked downregulation of key biosynthetic enzymes in RA metabolism, leading to a net decrease in intracellular RA levels. Exogenous RA supplementation attenuated TIC-induced expression of pro- and anti-inflammatory mediators, including IL-6, IL-8, nitric oxide, IL-10, and TGFβ. Mechanistically, RA suppressed these inflammatory responses by inhibiting NF-κB activation, likely through upstream attenuation of ERK and p38 MAPK pathways via upregulation of MAPK phosphatase 1 (MKP-1). In neuron and TIC-treated astrocyte co-cultures, RA treatment reduced the density of cleaved caspase 3-positive apoptotic-like neurons, an effect accompanied by decreased nitric oxide levels. These observations coincided with the restoration of mitochondrial integrity and mitophagy. Taken together, these findings identify RA metabolism as a key regulatory node in astrocyte reactivity and suggest a potential therapeutic role for RA in neuroinflammatory conditions.
Activation of 5-HT receptors in the ventrolateral orbital cortex alleviates neuropathic pain-induced depressive-like behaviors via GABAergic neurons in male rats.
Zhao YL, Yi HY, Hou XM … +9 more , La XC, Baba SS, Guo YX, Yao RR, Yuan XC, Zhang QR, Jia H, Wang YY, Huo FQ
Neurochem Int · 2026 · PMID 41720404 · Publisher ↗
Neuropathic pain is frequently comorbid with depression, which exacerbates patient suffering and complicates clinical management. Although the ventrolateral orbital cortex (VLO) is involved in pain processing and emotion...
Neuropathic pain is frequently comorbid with depression, which exacerbates patient suffering and complicates clinical management. Although the ventrolateral orbital cortex (VLO) is involved in pain processing and emotional regulation, its specific role in neuropathic pain-induced depression remains unclear. Emerging evidence implicates 5-HT receptors in modulating both pain and mood disorders via GABAergic transmission, yet their specific contributions in the VLO are not fully understood. Here, we aimed to investigate whether and how VLO 5-HT receptors mediate depressive-like behaviors associated with neuropathic pain in male rats. Using a spared nerve injury (SNI) model, combined with neuropharmacological, chemogenetic, and cell-type-specific adeno-associated virus (AAV) approaches, we found that activating VLO 5-HT receptor produced dose-dependent antidepressant effects, which were blocked by a selective antagonist. Mechanistically, 5-HT receptor-mediated antidepressant effects were enhanced by a GABA receptor antagonist and suppressed by a GABA receptor agonist. Chemogenetic activation of VLO GABAergic neurons abolished the antidepressant effects of 5-HT receptor stimulation. Furthermore, SNI-induced depressive-like behaviors correlated with reduced 5-HT receptor expression in the VLO. AAV-mediated 5-HT receptor overexpression specifically on GABAergic neurons alleviated depressive-like behaviors in SNI rats, while knockdown induced depressive-like phenotypes in wild-type rats. In conclusion, our findings demonstrate that 5-HT receptors in the VLO alleviate neuropathic pain-induced depressive-like behaviors through a GABAergic disinhibition mechanism. This study highlights 5-HT receptors in the VLO as promising therapeutic targets for mood disturbances associated with neuropathic pain, offering a cortical framework for comorbid pain-depression pathophysiology.
Assessing effects of microwave electromagnetic field in APP/PS1 mice by in vivo GABA-weighted imaging via variable delay multipulse-chemical exchange saturation transfer MRI.
Liu S, Cheng Y, Zhang X … +14 more , Shen Y, Wu S, Chen Y, Shi D, Zhuang C, Chen B, Zhong Y, Wang X, Wen Y, Zheng X, Jia Y, Guan J, Yan G, Wu R
Neurochem Int · 2026 · PMID 41713500 · Publisher ↗
Electromagnetic fields (EMFs) have been shown to be beneficial in treating Alzheimer's disease (AD), but the underlying neurophysiological mechanisms remain unclear. It has been proposed that EMF promotes GABAergic neuro...
Electromagnetic fields (EMFs) have been shown to be beneficial in treating Alzheimer's disease (AD), but the underlying neurophysiological mechanisms remain unclear. It has been proposed that EMF promotes GABAergic neurogenesis and that abnormal GABA levels are an important influence on the progression of AD. To achieve in vivo GABA-weighted imaging in the brain in APP/PS1 mice, we utilized variable delay multi-pulse (VDMP)-chemical exchange saturation transfer (CEST)- magnetic resonance imaging (MRI) and pathological validation to measure GABA levels in APP/PS1 mice under microwave EMF and explore the therapeutic mechanism. The APP/PS1 mice received a 4-week microwave EMF treatment. The findings show that microwave EMF stimulation significantly increased GABA-weighted signals on MRI of APP/PS1 mouse hippocampus. VDMP-CEST was sensitive in detecting GABA-weighted signals. ELISA showed that microwave EMF stimulation elevated GABA levels in the hippocampus. Compared to in vitro levels, VDMP-CEST accurately detected GABA-weighted signal changes. With the pathological validations, we found that microwave EMF exposure can elevate hippocampal GABA levels by promoting AQP4 polarizion, reducing Aβ accumulation and neuronal degeneration, improving cognitive impairment, and may have slowed AD progression. Collectively, microwave EMF treatment could increase GABA-related changes, which corresponded to the accumulation of Aβ and improvement in the water maze. VDMP-CEST detected levels are highly consistent with pathological evidence, implying that VDMP-CEST is an effective modality for in vivo GABA-weighted imaging during microwave EMF treatment, providing more objective imaging-based diagnostic evidence for monitoring GABA-related pathological changes in AD.
Vitamin B1 protects against Aβ-induced HIF-1α activation and neurotoxicity.
Anderson YT, Priest K, Zastre J
Neurochem Int · 2026 · PMID 41707701 · Publisher ↗
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and extensive neuronal loss, largely driven by amyloid beta (Aβ) accumulation and associated cellular stress. Vitami...
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and extensive neuronal loss, largely driven by amyloid beta (Aβ) accumulation and associated cellular stress. Vitamin B1 (thiamine) supplementation has demonstrated cognitive benefits in clinical AD studies, however, the mechanisms underlying thiamine's neuroprotective effects remain unclear. Here, we investigated whether thiamine mitigates Aβ-induced neurotoxicity by suppressing hypoxia-inducible factor-1 alpha (HIF-1α), a transcriptional stress factor regulating many proapoptotic and progressive amyloidogenic pathways. Exposure of neuronal cells to Aβ oligomers increased reactive oxygen species (ROS) accumulation, decreased intracellular Fe, and induced HIF-1α stabilization. HIF-1α activation by Aβ promoted apoptosis through increased endoplasmic reticulum (ER) stress and increased mitochondrial dimerization of BNIP3. Thiamine supplementation significantly reduced cellular ROS levels, preserved intracellular Fe levels, and restored prolyl hydroxylase (PHD) activity to promote HIF-1α hydroxylation and degradation. Suppression of HIF-1α by thiamine attenuated ER and BNIP3-driven apoptotic pathways and preserved neuronal viability. Thiamine further mitigated HIF-1α-mediated amyloidogenic progression, limiting feedback toxicity caused by Aβ. These results demonstrate that thiamine protects against Aβ-mediated neurotoxicity by reducing ROS, preserving Fe, and inhibiting HIF-1α-driven pathological cascades. Overall, this study identified a novel mechanism for thiamine's neuroprotective role, further supporting its therapeutic potential to limit neurodegenerative progression in AD.
APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice.
Roland NJ, Zigmond JW, Manganaro JE … +2 more , Daniel Estrella L, Stauch KL
Neurochem Int · 2026 · PMID 41692216 · Publisher ↗
Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with th...
Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD.
Calcineurin inhibition mitigates activation of enteric glia in vitro and affects their crosstalk with macrophages.
Patti A, Lipari CLR, Genazzani A … +2 more , Sortino MA, Merlo S
Neurochem Int · 2026 · PMID 41644014 · Publisher ↗
Multiple factors contribute to the physiopathology of inflammatory bowel diseases (IBD) and the enteric nervous system is emerging as a key player in this context. In particular, enteric glial cells (EGCs) share very sim...
Multiple factors contribute to the physiopathology of inflammatory bowel diseases (IBD) and the enteric nervous system is emerging as a key player in this context. In particular, enteric glial cells (EGCs) share very similar properties with central astrocytes, play a homeostatic function under basal conditions, but can be activated by inflammatory stimuli further contributing to mucosal damage. Calcineurin (CN) is an important mediator of astrocyte inflammation and has been described also in EGCs. The aim of this study was to establish an in vitro model of EGCs challenged with an inflammatory insult to better delineate the role of CN in their inflammatory reaction and interaction with immune cells. EGCs stimulated with LPS + ATP (5 μg/mL-2 mM) for 24 h showed typical inflammatory features with increased expression of the astrocyte marker GFAP, the inflammasome component NLRP3 and the alarmin HMGB1. Inhibition of CN by cyclosporin A (CsA, 1 μM) counteracted these effects and increased the expression of nuclear HMGB1. Nuclear translocation of NF-κB p65 induced by LPS + ATP was also blunted by CsA pre-treatment. The migration of RAW 264.7 macrophages co-cultured with LPS + ATP-stimulated EGCs was enhanced, an effect prevented by CsA. This was accompanied by activation of macrophages to a pro-inflammatory phenotype, as shown by increased COX-2, IL-1β and TNF-α gene expression. Inhibition of CN in EGCs reduced this response while increasing the phagocytic capacity of macrophages. Altogether the results here reported identify a central role for CN in the inflammatory response of EGCs and their crosstalk with cells of the immune system, supporting potential new sites of intervention for drugs targeting CN.
Short-term infusion of GDF11 after SCI attenuates pericytes loss and BSCB damage to promote recovery of spinal cord function.
Shen H, Liu J, Du M … +4 more , Qin G, Li J, Lu Y, Gao H
Neurochem Int · 2026 Feb · PMID 41644013 · Publisher ↗
To investigate the role of GDF11 in acute neural trauma, this study focused on the effects of GDF11 on pericytes and the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI). We established a mouse SCI mod...
To investigate the role of GDF11 in acute neural trauma, this study focused on the effects of GDF11 on pericytes and the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI). We established a mouse SCI model and administered GDF11 infusion for three consecutive days. Spinal cord samples were collected early after injury, and the integrity of the BSCB was evaluated using pathomorphological analysis, Western blotting, immunofluorescence, and transmission electron microscopy. The results demonstrated that GDF11 infusion significantly reduced BSCB damage at 7 days post-SCI, as evidenced by improved intercellular junction integrity and enhanced pericyte coverage. Since neurovascular communication is a critical function of the BSCB, we further assessed neuronal survival and myelin sheath integrity across different groups. In addition, we isolated primary central nervous system microvascular pericytes and simulated SCI through oxygen-glucose deprivation (OGD) culture, with and without GDF11 treatment and its critical receptor TGF-β receptor (TGFR) antagonist, ACE-536. The viability and migration ability of pericytes in each group were evaluated by flow cytometry and migration assays. We found that the GDF11/TGFR/SMAD3 signaling pathway mediates the beneficial effects of GDF11 on SCI. As functional recovery is a key measure of clinical outcome following SCI, behavioral assessments were performed at later stages. Our results showed that early GDF11 infusion significantly improved functional recovery, as demonstrated by enhanced gait performance and increased swimming scores. In conclusion, early post-SCI GDF11 infusion targeting pericytes to regulate BSCB integrity may offer a promising therapeutic approach for SCI recovery.
ERK-dependent astrocytic PAI-1 induction by influenza A virus disrupts the neurochemical balance of the PAI-1/tPA axis.
Park ES, Park BB, Kim RE … +3 more , Hong Y, Kwon KJ, Shin CY
Neurochem Int · 2026 · PMID 41638582 · Publisher ↗
BACKGROUND: Influenza A virus (IAV), although primarily a respiratory pathogen, is increasingly recognized to affect central nervous system (CNS) function. Astrocytes are key regulators of neurochemical homeostasis and n...
BACKGROUND: Influenza A virus (IAV), although primarily a respiratory pathogen, is increasingly recognized to affect central nervous system (CNS) function. Astrocytes are key regulators of neurochemical homeostasis and neuroinflammation, but the molecular pathways underlying their response to IAV remain incompletely defined. METHODS: Primary rat astrocytes were infected with wild-type IAV (PR8, H1N1) or PB1-F2-deficient IAV (PB1-F2[-]). Regulation of the plasminogen activator inhibitor-1 (PAI-1)/tissue-type plasminogen activator (tPA) system was examined by qPCR, Western blotting, zymography, and ELISA. ERK pathway activation was assessed using phospho-specific antibodies, and pathway dependency was tested using the ERK inhibitor U0126. Functional consequences on neurons were evaluated by neurite outgrowth assays using astrocyte-conditioned medium (ACM). RESULTS: IAV infection induced a robust increase in astrocytic PAI-1 expression and a marked reduction in tPA activity, accompanied by selective activation of ERK signaling. Pharmacological ERK inhibition completely abolished PAI-1 upregulation, indicating that ERK is required for this neurochemical shift. PB1-F2 deletion did not alter PAI-1 induction but partially modified cytokine expression profiles, demonstrating PB1-F2-independent regulation of the PAI-1/tPA axis. Compared with lipopolysaccharide (LPS), IAV elicited substantially lower cytokine levels yet induced markedly higher PAI-1 expression, suggesting a sustained antifibrinolytic phenotype. Neurons exposed to ACM from IAV-infected astrocytes exhibited reduced neurite extension and branching, indicating impaired neuronal structural development through paracrine mechanisms. CONCLUSIONS: IAV triggers an ERK-dependent induction of PAI-1 in astrocytes, leading to suppression of tPA activity and disruption of neuronal outgrowth. These findings identify a neurochemical mechanism linking astrocyte-specific MAPK signaling to neuroinflammatory and antifibrinolytic dysfunction during viral infection.
Involvement of α7 nicotinic acetylcholine receptor-signaling in social behavior impairments in the stressed mice.
Uchida M, Kano M, Ozaki N … +2 more , Yoshimi A, Noda Y
Neurochem Int · 2026 Feb · PMID 41564974 · Publisher ↗
Smoking is considered a form of self-medication for psychosis, including nicotine (NIC) dependence, through stimulation of the nicotinic acetylcholine receptors (nAChRs) in the central nervous system of patients with psy...
Smoking is considered a form of self-medication for psychosis, including nicotine (NIC) dependence, through stimulation of the nicotinic acetylcholine receptors (nAChRs) in the central nervous system of patients with psychiatric disorders. However, the effects of NIC on neuropsychological functions and the underlying molecular mechanisms remain unclear. We investigated the effects of (-)-NIC on emotional behaviors, expression of intracerebral nAChR subunits, and morphological changes in swim-stressed mice. Stressed mice showed social behavior impairments, low phosphorylation levels of Akt, CaMKII, and ERK, and reduced thickness of the pyramidal neuronal layer in the hippocampus. Acute or repeated administration of (-)-NIC (0.3 mg/kg, s.c.) to stressed mice attenuated social behavior impairments. Repeated administration of PHA568487, a selective α7 nAChR agonist, also attenuated these impairments. The attenuating effects of (-)-NIC were blocked by a selective α7 nAChR antagonist, but not by a selective α4β2 nAChR antagonist. Repeated administration of (-)-NIC ameliorated the reduced phosphorylation levels of Akt, CaMKII, and ERK, as well as morphological abnormalities in the hippocampus, without inducing conditioned place preference. Acute administration of (-)-NIC ameliorated the decreased Akt phosphorylation without affecting morphological abnormalities. Our findings suggest that hippocampal α7 nAChR signal pathways play an important role in social behavior impairments in stressed mice, and that abnormal neuronal morphology via these pathways contributes to the development of such impairments. Activation of α7 nAChRs was identified as a key target for new treatment strategies for emotional impairments in stress-related disorders.
Blood extracellular vesicles contribute to the exercise-mediated suppression of brain Aβ pathology in the App knockin mouse model of Alzheimer's disease.
Takeda A, Takeuchi T, Minakawa EN … +3 more , Tanaka N, Mochizuki H, Nagai Y
Neurochem Int · 2026 Feb · PMID 41548697 · Publisher ↗
Epidemiological, clinical, and experimental evidence suggest that physical exercise suppresses the deposition of amyloid β (Aβ) plaques in the brain and reduces the risk of Alzheimer's disease (AD). However, how exercise...
Epidemiological, clinical, and experimental evidence suggest that physical exercise suppresses the deposition of amyloid β (Aβ) plaques in the brain and reduces the risk of Alzheimer's disease (AD). However, how exercise provides such beneficial effects on AD remains largely unclear. In this study, we show that the exercise-mediated suppression of Aβ deposition requires blood extracellular vesicles (EVs) that are upregulated by exercise. We demonstrated that treadmill exercise induces a transient increase in the secretion of blood EVs in both wild-type mice and the App knockin mouse model of AD. Comprehensive analysis of protein contents of the exercise-induced blood EVs demonstrated that molecular chaperones, such as heat shock proteins and cochaperones, are substantially increased, together with substantial changes in proteomic profiles after exercise. Importantly, long-term exercise led to the suppression of Aβ plaque deposition in App knockin mice, but this suppressive effect was almost completely diminished by the pharmacological inhibition of EV secretion. These results indicate that the secretion of blood EVs is increased by exercise, which contributes to the suppression of Aβ pathology in the brain. Our study identifies blood EVs as a key mediator of the benefits of exercise throughout the body including the brain, highlighting the therapeutic potential of exercise-induced EVs for the treatment of AD pathology.
Sanguinarine alleviates pendimethalin-induced neurotoxicity via regulating microglial and neuroinflammatory pathways: An interplay of oxidative stress, apoptosis and microglial polarization.
Zhang K, Amir K, Mehreen A … +5 more , El Safadi M, Zia S, Jamil S, Al-Emam A, Hassan HM
Neurochem Int · 2026 Feb · PMID 41548696 · Publisher ↗
Pendimethalin (PMN) is a potent agrochemical that has shown severe neural alterations. Sanguinarine (SAN) is a naturally derived alkaloid that exhibits a wide range of biological properties. The current research was cond...
Pendimethalin (PMN) is a potent agrochemical that has shown severe neural alterations. Sanguinarine (SAN) is a naturally derived alkaloid that exhibits a wide range of biological properties. The current research was conducted to explore the palliative potential of SAN against PMN-induced neurotoxicity. Thirty-two Sprague Dawley rats were divided into the control, PMN (125 mg/kg), PMN (125 mg/kg) + SAN (15 mg/kg), and SAN (15 mg/kg) alone treated group. PMN intoxication upregulated the mRNA expressions of Aif1 (iba1), cd68, TNF-α, IL-10, IL-6, IL-1β, Nos2, Arg1, and Trem2 while inhibiting the mRNA expression of Tmem119. Neural tissues showed altered redox state after PMN exposure as evidenced by escalated levels of ROS and MDA coupled with marked declined in the activities of HO-1, GPx, CAT, GSR, SOD, and GST. Additionally, PMN administration provoked a sharp decline in the levels of NGF, BDNF, GDNF, Synaptophysin, and PSD-95. Moreover, exposure of PMN elevated the levels of Caspase-9, Bax, and Caspase-3 coupled with a significant reduction in the levels of Bcl-2. Neural tissues showed severe morphological alterations including vacuolar degeneration, neuronal loss, microglial activation, apoptotic bodies, capillary congestion, perineuronal vacuolation, and neural edema after PMN intoxication. Importantly, SAN supplementation notably alleviated neural damage via suppressing the activation of microglial and inflammatory pathways along with regulating redox profile, apoptotic indices, and histopathological alterations. Our in-silico assessment showed excellent binding affinity of SAN with key regulatory proteins thereby suggesting its critical role in suppressing the activation of microglial cells.
Swertisin improves Alzheimer's disease-like pathology in 5XFAD male mice through regulation in plasmin activity.
Moon S, Kwon H, Cho E … +7 more , Lee S, Park SJ, Moon M, Ryu JH, Jang DS, Bae HJ, Kim DH
Neurochem Int · 2026 Feb · PMID 41520885 · Publisher ↗
Abnormal accumulation of amyloid β (Aβ), which may result from excessive production or impaired clearance, is one of the pathomechanisms of Alzheimer's disease (AD). Plasmin is one of the important proteases involved in...
Abnormal accumulation of amyloid β (Aβ), which may result from excessive production or impaired clearance, is one of the pathomechanisms of Alzheimer's disease (AD). Plasmin is one of the important proteases involved in the Aβ clearance system. In this study, we investigated whether swertisin can regulate plasmin activity and reduce Aβ pathology. First, we examined whether swertisin regulated plasmin activity, mature brain-derived neurotrophic factor (mBDNF) levels, and plasminogen activator inhibitor-1 (PAI-1) activity in vitro. Next, we assessed the effect of swertisin on memory impairments in an Aβ-injected AD-like mouse model and in 5XFAD mice. To evaluate the involvement of plasmin in the effect of swertisin in the Aβ-injected AD-like mouse model, we used 6-aminocaproic acid (6-AA), a plasmin inhibitor. Additionally, we measured plasmin activity and mBDNF levels in the hippocampus of Aβ-injected AD-like mice and 5XFAD mice. Swertisin increased plasmin activity and mBDNF levels in hippocampal slices from both normal and 5XFAD mice. Moreover, swertisin ameliorated Aβ-induced synaptic long-term potentiation (LTP) deficits in hippocampal slices. Swertisin also mitigated memory impairments induced by ventricular injection of Aβ, and this effect was blocked by 6-AA. Furthermore, swertisin improved learning and memory in 5XFAD mice while reducing Aβ deposition and neuroinflammation. This study demonstrates that swertisin ameliorates AD-like pathology by regulating plasmin activity. Plasmin activated by swertisin may cleave Aβ aggregates and increase mBDNF levels, thereby protecting the brain from Aβ toxicity. Swertisin may represent an effective therapeutic strategy for AD patients.
Neuromodulatory effects of dual-site repetitive transcranial magnetic stimulation targeting frontal and temporal cortices in subjective tinnitus: A functional magneti resonance imaging study.
Wen F, Yang X, Jing G … +4 more , Yu L, Mou C, Ran J, Zhang Y
Neurochem Int · 2026 Feb · PMID 41520884 · Publisher ↗
OBJECTIVE: This study investigated the neurofunctional effects of frontotemporal dual-site repetitive transcranial magnetic stimulation (rTMS) in patients with subjective tinnitus (ST). METHODS: Ninety ST patients were r...
OBJECTIVE: This study investigated the neurofunctional effects of frontotemporal dual-site repetitive transcranial magnetic stimulation (rTMS) in patients with subjective tinnitus (ST). METHODS: Ninety ST patients were randomly assigned to active (n = 45) or sham (n = 45) with rTMS. Fifty-two healthy subjects served as controls. All underwent resting-state fMRI (rs-fMRI) and clinical assessment (Tinnitus Handicap Inventory, THI) before and after a two-week intervention. Brain metrics included regional homogeneity (ReHo), fractional amplitude of low-frequency fluctuations (fALFF), degree centrality (DC), functional connectivity (FC), and structural covariance networks (SCN). RESULTS: Active rTMS significantly reduced THI scores (P < 0.001). Rs-fMRI showed decreased ReHo in the right inferior parietal lobule, decreased fALFF in the right superior temporal gyrus (STG), but increased fALFF in the right temporal pole, and reduced DC in the right middle temporal gyrus (MTG) (all P < 0.05). FC weakened between right STG-MTG and right MTG-occipital gyrus (P < 0.05). SCN nodal centrality changed in right STG and left MTG (P < 0.05). No such changes were seen in sham or control groups (all P > 0.05). CONCLUSION: Frontotemporal dual-site rTMS alleviates tinnitus, likely by modulating activity and connectivity in auditory and cross-modal integration regions, involving the default mode and auditory-visual processing networks.
Receptor tyrosine kinases in Alzheimer's disease: Mechanistic insights and therapeutic implications.
Zhao P, Cao Z, Rozpędek-Kamińska W
Neurochem Int · 2026 Feb · PMID 41519166 · Publisher ↗
Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis remains incompletely understood. It is considered one of the most costly, fatal, and socially burdensome diseases of the twenty-first ce...
Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis remains incompletely understood. It is considered one of the most costly, fatal, and socially burdensome diseases of the twenty-first century. Previous studies have shown that receptor tyrosine kinases (RTKs) play an important role in the pathological progression of AD. RTKs regulate amyloid-beta (Aβ) deposition and Tau hyperphosphorylation, thereby influencing neuronal survival, synaptic plasticity, and spatial cognitive function in patients with AD. From a therapeutic perspective, RTK-targeted interventions offer new avenues for AD treatment. Inhibiting specific RTKs can reduce Aβ production and pathological Tau phosphorylation, thereby slowing disease progression. Conversely, activating selected neuroprotective RTKs can promote neuronal survival, restore synaptic function, and ameliorate cognitive impairment. Several small-molecule inhibitors and monoclonal antibodies targeting RTKs have already demonstrated promising therapeutic potential in preclinical studies. Overall, this review systematically summarizes the clinical features and mechanisms of AD, as well as the current applications and future challenges of RTK-based research in neurodegenerative diseases, providing theoretical guidance for the development and repurposing of novel multi-pathway RTK-directed therapies.
24-Hydroxycholesterol suppresses steroid 5α-reductase-catalyzed conversion in human glioblastoma cell lines: A novel link between brain cholesterol homeostasis and androgen metabolism.
Wikvall K, Olsson F, Wåhlén E … +4 more , Roy A, Ubhayasekera SJKA, Bergquist J, Norlin M
Neurochem Int · 2026 Feb · PMID 41506415 · Publisher ↗
Glioblastoma is the most aggressive primary brain tumor in adults. Androgens are reported to influence the development of glioblastoma. Dihydrotestosterone (DHT) is formed from testosterone by action of the enzyme steroi...
Glioblastoma is the most aggressive primary brain tumor in adults. Androgens are reported to influence the development of glioblastoma. Dihydrotestosterone (DHT) is formed from testosterone by action of the enzyme steroid 5α-reductase and is the most potent growth-inducing androgen metabolite. 24-Hydroxycholesterol, another steroid in the brain, is pivotal for brain cholesterol homeostasis and has been suggested to influence glioblastoma cells. However, a connection between 24-hydroxycholesterol and androgen metabolism related to glioblastoma has not previously been reported. The present study reports that human T98G glioblastoma cells metabolize testosterone into DHT, 3α-androstanediol and androstenedione. The 5α-reductase pathway converted testosterone to DHT and further to 3α-androstanediol. The 17β-hydroxysteroid dehydrogenase pathway metabolized testosterone to androstenedione. Results indicated that the 5α-reductase pathway is the major pathway for testosterone metabolism in this cell line. 24-Hydroxycholesterol significantly suppressed the conversion of testosterone to DHT and 3α-androstanediol, to a similar degree as the synthetic 5α-reductase inhibitor finasteride. Suppression of DHT formation resulted in increased metabolism to androstenedione. Similar effects on DHT formation were observed with the LXR agonist T0901317 as with 24-hydroxycholesterol. In addition, 24-hydroxycholesterol suppressed DHT formation in patient-derived primary GB cell lines U3009 and U3013, indicating that the observed connection between 24-hydroxycholesterol and androgen metabolism is not unique for T98G cells. Furthermore, 24-hydroxycholesterol-mediated suppression of DHT formation was also observed in human neuroblastoma SH-SY5Y cells. To summarize, the present data provide information on androgen metabolism in glioblastoma cells and indicate a previously unknown link between cholesterol homeostasis and growth-inducing androgens in glioblastoma and potentially other cell types.
Redox-sensitive high mobility group box 1 (HMGB1) protein is a multipotent regulator in the pathogenesis of Alzheimer's disease.
Salminen A
Neurochem Int · 2026 Feb · PMID 41500468 · Publisher ↗
The primary cause of Alzheimer's disease (AD) is still unknown although genetic studies have identified several risk genes and significant alterations in the chromatin landscape. These genetic changes are associated with...
The primary cause of Alzheimer's disease (AD) is still unknown although genetic studies have identified several risk genes and significant alterations in the chromatin landscape. These genetic changes are associated with neuroinflammation and clear signs of neurodegeneration and cognitive impairment. While the redox-sensitive high mobility group box 1 (HMGB1) protein is a chromatin binding chaperone which maintains the integrity of chromatin, it is also a stress-induced alarmin factor released from the nucleus and subsequently secreted into extracellular space where it is a major inducer of inflammatory responses. There is abundant evidence that HMGB1 is a multifunctional regulator of AD pathology because it can (i) stimulate neuroinflammatory responses, (ii) disrupt the blood-brain barrier, (iii) inhibit microglial clearance of β-amyloid deposits, (iv) trigger cellular senescence and induce cell death, and (v) stimulate synapse loss and cognitive impairment. Experiments with transgenic AD mice have revealed that a release of HMGB1 from nuclei and its secretion promoted neuroinflammation and aggravated AD pathology. Conversely, it is known that the inhibition of HMGB1 expression or its nuclear release attenuated neuroinflammation and delayed the pathological changes in transgenic AD mice. Given that there are many drugs which can inhibit HMGB1-induced inflammatory states, it seems that HMGB1 is a promising therapeutic target to suppress AD pathogenesis.
USP53 promotes NOTCH2-induced neuroinflammation in Alzheimer's disease.
He D, Zhao H, Zhu Y … +8 more , Kou Y, Liu T, Huang H, Yang H, Zhang L, Deng J, Xu F, Wang Q
Neurochem Int · 2026 Feb · PMID 41482165 · Publisher ↗
PURPOSE: This study aimed to investigate the role of USP53 and its associated signaling pathway associated with USP53 in Alzheimer's disease (AD). METHODS: In vivo experiments were conducted in C57BL/6, 5XFAD, and USP53-...
PURPOSE: This study aimed to investigate the role of USP53 and its associated signaling pathway associated with USP53 in Alzheimer's disease (AD). METHODS: In vivo experiments were conducted in C57BL/6, 5XFAD, and USP53-knockout 5XFAD (USP53) mice. In vitro experiments were performed using primary human microglia cells. mRNA expression was examined using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Protein expression was measured using western blotting and immunofluorescence (IF). Immunoprecipitation (Co-IP) was used to detect protein-protein interactions. Morris Water Maze (MWM) was used to evaluate the learning ability and memory of mice. RESULTS: USP53 was overexpressed in patients with AD. Knockout of USP53 downregulated the expression of CD68, glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and neuronal nuclear protein (NeuN), as well as the inflammatory mediators, interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The accumulation of Tau protein was reduced, and the learning ability and memory was improved in USP53 mice compared to 5XFAD mice. In vitro experiments demonstrated that protein-protein interaction existed between USP53 and NOTCH2 and that the inhibition of USP53 prevented amyloid-beta (Aβ)-induced deubiquitination of NOTCH2. Knockdown of USP53 reduced Aβ-induced elevation of inflammatory mediators and repressed Aβ-induced activation of IKKβ/NFκB signaling pathway in microglia. CONCLUSION: USP53 promotes the activation of neuroinflammation and worsens learning ability and memory in AD mice, mediated by NOTCH2.
Alcohol disrupts neural differentiation through endoplasmic reticulum stress and PERK pathway activation.
Zhang Z, Wen W, Lin H … +3 more , Hu D, Li H, Luo J
Neurochem Int · 2026 Jan · PMID 41475444 · Publisher ↗
Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying mole...
Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line derived from the mouse embryonic brain, were utilized as an in vitro model. As an in vivo model, pregnant mice were exposed to alcohol between gestation days 14 and 16, after which newly formed neurons in the ventricular zone (VZ) were analyzed. To examine the role of endoplasmic reticulum (ER) stress, tunicamycin (TM), and MANF-deficient NE-4C cells were employed. Neural differentiation was assessed using immunofluorescence, immunoblotting and flow cytometry. Alcohol impaired the differentiation of NE-4C cells into neurons and astrocytes without impacting cell migration. It also induced ER stress, preferably activating the PERK pathway. Similarly, ER stress caused by TM and MANF deficiency disrupted neural differentiation and activated PERK. Inhibiting PERK mitigated alcohol-induced impairment of neuronal differentiation. PAE decreased the number of newly formed neurons in the VZ of fetal brain while having little effects on cell survival and proliferation. Inhibiting PERK partially reversed the reduction of new neurons caused by PAE. Thus, alcohol-induced ER stress, particularly PERK activation, may contribute to impaired neurogenesis linked to FASD.
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