Acetylated tau exacerbates learning and memory impairment by disturbing with mitochondrial homeostasis

Redox Biology, Journal Year: 2023, Volume and Issue: 62, P. 102697 - 102697

Published: April 6, 2023

Increased tau acetylation at K274 and K281 has been observed in the brains of Alzheimer's disease (AD) patients animal models, mitochondrial dysfunction are noticeable early features AD. However, effect acetylated on mitochondria unclear until now. Here, we constructed three type forms, mutant by mutating its K274/K281 into Glutamine (TauKQ) to mimic disease-associated lysine acetylation, non-acetylation Arginine (TauKR) wild-type human full-length (TauWT). By overexpression these forms vivo vitro, found that, TauKQ induced more severe cognitive deficits with neuronal loss, dendritic plasticity damage dysfunctions than TauWT. Unlike TauWT fusion, not only fission decreasing mitofusion proteins, but also inhibited biogenesis via reduction PGC-1a/Nrf1/Tfam levels. TauKR had no significant difference abnormalities compared Treatment BGP-15 rescued impaired learning memory attenuation dysfunction, loss complexity damage, which caused TauKQ. Our data suggested K274/281 was an important post translational modification site for neurotoxicity, is a potential therapeutic drug

Language: Английский

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SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: July 22, 2023

Abstract Background Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked mitochondrial dysfunction, most likely as a consequence excessive formation mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), key NAD + -dependent deacetylase, critical responsible for functional homeostasis highly neuropathology. However, the role SIRT3 in regulating MAM coupling remains unknown. Methods Streptozotocin-injected diabetic mice high glucose-treated SH-SY5Y cells were established animal cellular models, respectively. expression was up-regulated vivo using adeno-associated virus mouse hippocampus vitro recombinant lentivirus vector. Cognitive function evaluated behavioural tests. Hippocampus injury assessed Golgi Nissl staining. Apoptosis analysed western blotting TUNEL assay. Mitochondrial detected flow cytometry confocal fluorescence microscopy. The mechanisms investigated co-immunoprecipitation VDAC1–GRP75–IP3R complex, imaging ER co-localisation transmission electron microscopy structural analysis MAMs. Results Our results demonstrated that significantly reduced hippocampal tissues from mice. Further, up-regulating alleviated injuries impairment mitigated Ca 2+ overload-induced dysfunction apoptosis. Mechanistically, enhanced under glucose conditions, which reversed by genetic up-regulation via interaction complex vivo. Furthermore, we therapeutic effects pharmacological activation honokiol treatment, exhibited similar to our interventions. Conclusions In summary, findings suggest ameliorates limiting aberrant formation. targeting provides promising candidate diabetes-associated dysfunction. Overall, study suggests novel indicates SIRT3-targeted therapies dementia patients.

Language: Английский

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The emerging role of autophagy and mitophagy in tauopathies: From pathogenesis to translational implications in Alzheimer’s disease

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Oct. 17, 2022

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, affecting more than 55 million individuals worldwide in 2021. In addition to “amyloid hypothesis,” an increasing number of studies have demonstrated that phosphorylated tau plays important role AD pathogenesis. Both soluble oligomers and insoluble aggregates brain can induce structural functional neuronal damage through multiple pathways, eventually leading memory deficits neurodegeneration. Autophagy cellular response various stress stimuli generally be categorized into non-selective selective autophagy. Recent indicated both types autophagy are involved pathology. Among several subtypes autophagy, mitophagy, which mediates removal mitochondria, has attracted attention because dysfunctional mitochondria been suggested contribute tauopathies. this review, we summarize latest findings on bidirectional association between abnormal proteins defective as well might constitute a vicious cycle induction Neuroinflammation, another feature pathogenesis progression AD, shown crosstalk with mitophagy. Additionally, comprehensively discuss relationship neuroinflammation, By elucidating underlying molecular mechanisms governing these pathologies, highlight novel therapeutic strategies targeting mitophagy such those using rapamycin, urolithin, spermidine, curcumin, nicotinamide, actinonin, for prevention treatment AD.

Language: Английский

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Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer’s Disease (Type 3 Diabetes)

Journal of Alzheimer s Disease, Journal Year: 2023, Volume and Issue: 95(4), P. 1301 - 1337

Published: Sept. 12, 2023

Malignant brain aging corresponds to accelerated age-related declines in functions eventually derailing the self-sustaining forces that govern independent vitality. establishes path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction neurons, oligodendrocytes, astrocytes, microglia, and microvascular systems, is mechanistically driven by insulin insulin-like growth factor (IGF) deficiencies resistances with accompanying deficits energy balance, increased cellular stress, inflammation, impaired perfusion, mimicking core features diabetes mellitus. underlying pathophysiological derangements result mitochondrial dysfunction, abnormal protein aggregation, oxidative endoplasmic reticulum aberrant autophagy, post-translational modification proteins, all which are signature both dysregulated insulin/IGF-1-mechanistic target rapamycin (mTOR) signaling. This article connects dots from benign malignant neurodegeneration reviewing salient pathologies associated initially adaptive later dysfunctional mTOR signaling brain. Effective therapeutic preventive measures must be two-pronged designed 1) address complex shifting impairments through re-purpose effective anti-diabetes therapeutics brain, 2) minimize impact extrinsic mediators transitions, e.g., inflammatory states, obesity, systemic resistance diseases, repeated bouts general anesthesia, minimizing exposures or implementing neuroprotective measures.

Language: Английский

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Melatonin Attenuates Sepsis-Induced Acute Lung Injury via Inhibiting Excessive Mitophagy

Drug Design Development and Therapy, Journal Year: 2023, Volume and Issue: Volume 17, P. 2775 - 2786

Published: Sept. 1, 2023

Epidemiological studies have indicated that lung injury is a frequent complication of sepsis. Mitophagy vital to multiple pathological processes and diseases; however, its influence on sepsis-induced acute remains elusive. Melatonin has antioxidant action anti-inflammatory effects, including regulating mitophagy inflammatory cytokine expression. Whereas, little known about the affection melatonin CLP-induced ALI.The in vivo effect OPTN-mediated was studied by ALI mouse model using C57BL/6 followed treatment with vehicle (30 mg/kg/d, intraperitoneal injection). assayed wet /dry ratio, hematoxylin eosin staining, immunohistochemical staining. Signaling pathway changes were subsequently determined Western blotting immunofluorescence The effects STAT3 activation TNF-α production detected blotting, PCR, staining.Our results OPTN, adaptors significantly repressed ALI, accompanied overactivation inflammation. At same time, we found alleviated caused CLP, highly correlated OPTN-related mitophagy. Furthermore, demonstrated mitophagy, which normalized melatonin, blocked involved epithelial barrier inflammation vivo.Overall, our confirm adjusted ALI. Moreover, manipulation through could be possible reduce sepsis-associated injury.

Language: Английский

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Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson’s Disease Models by Alleviating Oxidative Stress

Antioxidants, Journal Year: 2023, Volume and Issue: 12(1), P. 153 - 153

Published: Jan. 9, 2023

Parkinson's disease (PD) is the second most common neurodegenerative characterized by progressive loss of dopaminergic neurons in substantia nigra midbrain. The etiology PD has yet to be elucidated, and remains incurable. Increasing evidence suggests that oxidative stress key causative factor PD. Due their capacity alleviate stress, antioxidants hold great potential for treatment Vitamins are essential organic substances maintaining life organisms. Vitamin deficiency implicated pathogenesis various diseases, such as In present study, we investigated whether administration vitamin B12 (VB12) could ameliorate phenotypes vitro vivo. Our results showed VB12 significantly reduced generation reactive oxygen species (ROS) rotenone-induced SH-SY5Y cellular model. a Parkin gene knockout C. elegans model, mitigated motor dysfunction. Moreover, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse also displayed protective effects, including rescue mitochondrial function, neuron loss, movement disorder. summary, our suggest supplementation may novel method intervention PD, which safer more feasible than chemical drug treatment.

Language: Английский

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Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: 168(3), P. 288 - 302

Published: Jan. 26, 2024

Abstract An increase in tau acetylation at K274 and K281 abnormal mitochondrial dynamics have been observed the brains of Alzheimer's disease (AD) patients. Here, we constructed three types plasmids, TauKQ (acetylated mutant, by mutating its K274/K281 into glutamine to mimic disease‐associated lysine acetylation), TauKR (non‐acetylated arginine), TauWT (wild‐type human full‐length tau). By transfecting these plasmids HEK293 cells, found that induced fusion increasing level proteins. Conversely, fission reducing proteins, exacerbating dysfunction apoptosis. BGP‐15 ameliorated TauKQ‐induced apoptosis improving dynamics. Our findings suggest K274/281 represents an important post‐translational modification site regulating dynamics, holds potential as a therapeutic agent for mitochondria‐associated diseases such AD. image

Language: Английский

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Upregulation of ISG15 induced by MAPT/tau accumulation represses autophagic flux by inhibiting HDAC6 activity: a vicious cycle in alzheimer disease

Autophagy, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by deficit macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as regulator of selective autophagy ataxia telangiectasia (A-T), its role AD remains unexplored. Our study reveals elevated levels brains patients with sporadic and models vivo vitro. overexpression cells hippocampus inhibited HDAC6 (histone deacetylase 6) activity through C-terminal LRLRGG binding HDAC6. Consequently, this increased CTTN (cortactin) acetylation, disrupted F-actin recruitment lysosomes, impaired autophagosome (AP)-lysosome (LY) fusion. These disruptions led accumulation, synaptic damage, neuronal loss, cognitive deficits. Conversely, knockdown our HsMAPT (human MAPT) pathology model restored activity, promoted AP-LY fusion, improved function. This identifies key autophagic flux AD, suggesting that targeting ISG15-mediated could offer therapeutic potential for AD.

Language: Английский

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<italic>MCU</italic> knockdown in hippocampal neurons improves memory performance of an Alzheimer’s disease mouse model

Acta Biochimica et Biophysica Sinica, Journal Year: 2022, Volume and Issue: 54(10), P. 1528 - 1539

Published: Sept. 1, 2022

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive decline, which could be promoted mitochondrial dysfunction induced Ca 2+ (mCa 2+) homeostasis Mitochondrial calcium uniporter (MCU), key channel of mCa uptake, may target for AD treatment. In the present study, we reveal first time that MCU knockdown in hippocampal neurons improves memory performance APP/PS1/tau mice through radial arm maze task. Western blot analysis, transmission electron microscopy (TEM), Golgi staining, immunohistochemistry (IHC) ELISA results demonstrate upregulates levels postsynaptic density protein 95 (PSD95) synaptophysin (SYP), increases numbers synapses dendritic spines. Meanwhile, decreases neuroinflammatory response astrogliosis high IL-1β TNF-α, PINK1-Parkin mitophagy signaling pathway level Beclin-1 but P62. addition, recovers average volume number mitochondria. These data confirm ameliorating synapse structure function, relieving inflammation recovering mitophagy, indicating inhibition has potential to developed as novel therapy AD.

Language: Английский

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Autophagy regulation and protein kinase activity of PIK3C3 controls sertoli cell polarity through its negative regulation on SCIN (scinderin)

Autophagy, Journal Year: 2023, Volume and Issue: 19(11), P. 2934 - 2957

Published: July 14, 2023

Sertoli cells are highly polarized testicular that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III phosphatidylinositol 3-kinase (PtdIns3K) plays core roles in macroautophagy various types; however, its role remains unclear. Here, we generated mouse line which the gene encoding catalytic subunit, Pik3c3, was specifically deleted (cKO) found after one round of normal spermatogenesis, cKO mice quickly became infertile showed disruption polarity impaired spermiogenesis. Subsequent proteomics phosphoproteomics analyses enriched F-actin cytoskeleton network involved disorganized Sertoli-cell structure testis identified significant increase negative regulator SCIN (scinderin) reduced phosphorylation HDAC6, an α-tubulin deacetylase. Our results further demonstrated accumulation caused disorder disassembly cytoskeleton, related to failure degradation through autophagy-lysosome pathway. Additionally, HDAC6 at site S59 by PIK3C3 essential ubiquitin-proteasome As result, accumulated deacetylated K189 led cytoskeleton. Taken together, our findings elucidate new mechanism maintaining cells, both autophagy regulation or protein kinase activities required stabilization actin cytoskeleton.Abbreviations: ACTB: actin, beta; AR: androgen receptor; ATG14: 14; BafA1: bafilomycin A1; BECN1: beclin 1, related; BTB: blood-testis barrier; CASP3: caspase 3; CDC42: division cycle 42; CDH2: cadherin 2; CHX: cycloheximide; CTNNA1: catenin (cadherin associated protein), alpha 1; CYP11A1: cytochrome P450, family 11, subfamily A, polypeptide EBSS: Earle's balanced salt solution; ES: ectoplasmic specialization; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCNA: nuclear acidic protein; GJA1: gap junction protein, H2AX: H2A.X variant histone; HDAC6: histone deacetylase 6; KIT: KIT proto-oncogene, receptor tyrosine kinase; LAMP1: lysosomal membrane MAP3K5: mitogen-activated 5; MAP1LC3B: microtubule 1 light chain 3 OCLN: occludin; PIK3C3: subunit type PIK3R4: phosphoinositide-3-kinase regulatory 4; PNA: arachis hypogaea lectin; RAC1: Rac small GTPase SCIN: scinderin; SQSTM1/p62: sequestosome SSC: spermatogonia stem cell; STK11: serine/threonine 11; TJP1: tight TubA: tubastatin A; TUBB3: tubulin beta III; TUNEL: TdT-mediated dUTP nick-end labeling; UB: ubiquitin; UVRAG: UV radiation resistance gene; VIM: vimentin; WT1: WT1 transcription factor; ZBTB16: zinc finger BTB domain containing 16.

Language: Английский

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