Tau induces inflammasome activation and microgliosis through acetylating NLRP3.

BACKGROUND: Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule-associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. METHODS: The levels of nucleotide-binding oligomerisation domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme-linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test-tube acetylation assay, co-immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau-overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno-associated virus injection. The cognitive functions of Tau-overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba-1 IF staining and [18F]-DPA-714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau-NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. RESULTS: Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg-AD mice, microtubule-associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of 'early' phosphorylated-Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau-K18 domain acetyltransferase activity-dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV-2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau-NLRP3-binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. CONCLUSIONS: In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies.

Exerkine ß-aminoisobutyric acid protects against atrial structural remodeling and atrial fibrillation in obesity via activating AMPK signaling and improving insulin sensitivity.

Moderate exercise decreases the risk for atrial fibrillation (AF), an effect which is probably mediated via exercise-stimulated release of exerkines. ß-Aminoisobutyric acid (BAIBA), a novel exerkine, has been reported to provide protective benefits against many cardiovascular diseases, yet its role in AF remains elusive. Herein, using a mouse model of obesity-related AF through high-fat diet (HFD) feeding, we found that 12-week drinking administration of BAIBA (170 mg/kg/day) decreased AF susceptibility in obese mice. Atrial remodeling assessment showed that BAIBA attenuated obesity-induced atrial hypertrophy and interstitial fibrosis, thereby ablating the substrate for AF. Of note, to our knowledge, this is the first report of the direct association of BAIBA and hypertrophy. BAIBA has been reported to be a key regulator of glucose and lipid metabolism, and we found that BAIBA alleviated insulin resistance in obese mice. Transcriptional analysis of metabolism-related genes showed that BAIBA increased the transcription of fatty acids metabolism-related genes in the atria of lean mice but not in that of obese mice. Mechanistic investigation showed that BAIBA stimulated AMP-activated protein kinase (AMPK) signaling in the atria of obese mice and palmitic acid (PA)-treated neonatal rat cardiomyocytes (NRCM), whereas inhibition of AMPK via Compound C attenuated BAIBA-conferred cardioprotection against hypertrophy and insulin resistance in PA-treated NRCM. Collectively, BAIBA attenuates AF susceptibility in obese mice via activated AMPK signaling and resultant improvement of insulin sensitivity, thereby providing perspectives on the potential therapeutic role of BAIBA in AF treatment.

Effect of a Self-Assembled Nucleating Agent on the Crystallization Behavior and Spherulitic Morphology of Poly(lactic acid).

Herein, decanedioic acid dibenzoylhydrazide (DDBH) was used as a nucleating agent to improve the crystallization of poly(lactic acid) (PLA). The formation of DDBH assemblies in PLA melts at different concentrations was systematically investigated. The DDBH (0.5-0.9 wt %) recrystallized as dendrite-like structures during the isothermal crystallization process, and the crystal morphology of PLA underwent a morphological change from spherical form to a similar dendritic crystal form. Differential scanning calorimetry and in situ wide-angle X-ray diffraction analysis results showed that crystallizability and overall crystallization rate of PLA were enhanced by the addition of DDBH. The half-crystallization time at 120 °C reduced to 0.28 min compared to pure PLA (6.12 min), after adding 0.9 wt % DDBH. Moreover, the crystallinity and lamellar thickness of crystalline PLA increased, while the size of the microcrystal of PLA decreased with an increase in DDBH content. The heat deflection temperatures of PLA/DDBH blends increased and hence heat resistance improved.

Super-tough polylactic acid (PLA)/poly(butylene succinate) (PBS) materials prepared through reactive blending with epoxy-functionalized PMMA-GMA copolymer.

High-performance biosourced polylactic acid (PLA)/poly(butylene succinate) (PBS) blends with small amounts of compatibilizer, epoxy-functionalized methyl methacrylate-co-glycidyl methacrylate copolymer (PMMA-GMA), were fabricated by melt compounding. The properties of the modified PLA/PMMA-GMA, PBS/PMMA-GMA, and PLS(PLA/PBS)/PMMA-GMA blends were investigated systematically. DSC combined with X-ray diffraction revealed a low-order semi-crystalline structure for all samples. SEM and DMA showed that the compatibility between PLA and PBS was improved after addition of PMMA-GMA. Rheological behavior of blends showed that the addition of PMMA-GMA resulted in a significant improvement in the viscoelasticity. FT-IR spectra confirmed that the interfacial compatibilization between PLA and PBS phases was improved due to the reaction of epoxy groups with terminal groups of PLA and PBS. Finally, the toughness and notched impact strength of the PLA materials were increased significantly. The elongation at break and notched impact strength of PLS/PMMA-GMA was about 55.7 and 6.2 times than neat PLA after incorporation of 7 wt% PMMA-GMA, respectively.

PCSK9 attenuates efferocytosis in endothelial cells and promotes vascular aging.

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds to low-density lipoprotein receptors. Efferocytosis is the process by which phagocytes remove apoptotic cells. Both PCSK9 and efferocytosis play important roles in regulating redox biology and inflammation, the key factors contributing to vascular aging. This study was designed to investigate the impact of PCSK9 on efferocytosis in endothelial cells (ECs) and its implications in vascular aging. Methods and Results: Studies were performed in primary human aortic ECs (HAECs) and primary mouse aortic ECs (MAECs) isolated from male wild-type (WT) and PCSK9-/- mice, and in young and aged mice treated with saline or the PCSK9 inhibitor Pep2-8. Our findings include that recombinant PCSK9 protein induces defective efferocytosis and aging marker senescence-associated-ß-galactosidase (SA-ß-gal) expression in ECs, while PCSK9-/- restores efferocytosis and inhibits SA-ß-gal activity. Further studies in aged mice showed that endothelial deficiency of MerTK, a critical receptor for efferocytosis that allows phagocytes to detect the presence of apoptotic cells, may be an indicator of vascular dysfunction in the aortic arch. Pep2-8 treatment markedly restored efferocytosis in endothelium from the aged mice. A proteomics study in the aortic arch from aged mice revealed that Pep2-8 administration significantly downregulates expression of NOX4, MAPK subunits, NF-κB, and secretion of pro-inflammatory cytokines, all known to promote vascular aging. Immunofluorescent staining showed that Pep2-8 administration upregulates expression of eNOS and downregulates expression of pro-IL-1ß, NF-κB and p22phox compared to saline treated group. Conclusions: These findings provide initial evidence for the ability of aortic ECs to accomplish efferocytosis and argue for a role of PCSK9 in attenuating EC efferocytosis, thereby leading to vascular dysfunction and acceleration in vascular aging.

Microglia activation mediates circadian rhythm disruption-induced cognitive impairment in mice.

Alzheimer's disease (AD) is the leading cause of dementia and there are no effective treatments for this disease currently. Circadian rhythm disruption (CRD) is a hallmark of modern society that appears to be on the rise. It is well reported that AD is associated with disrupted circadian functioning and CRD can impair cognitive function. However, the cellular mechanisms underlying CRD-associated cognitive decline remain elusive. In this study, we investigated whether microglia are involved in CRD-induced cognitive decline. We established experimental 'jet lag' (phase delay of the light/dark cycles)-induced CRD mouse model and observed significant impairment of spatial learning and memory function in these mice. In the brain, CRD resulted in neuroinflammation, which was characterized by microglia activation and increased pro-inflammatory cytokine production, impairments in neurogenesis and reduction of synaptic proteins in the hippocampus. Interestingly, elimination of microglia with the colony stimulating factor-1 receptor inhibitor PLX3397 prevented CRD-induced neuroinflammation, cognitive decline, impairment of neurogenesis and loss of synaptic proteins. These findings collectively suggest that microglia activation plays a key role in CRD-induced cognitive deficit most likely through neuroinflammation-mediated impairments in adult neurogenesis and synapses.

Image-Based Methods to Study Membrane Trafficking Events in Stomatal Lineage Cells.

In eukaryotic cells, membrane components, including proteins and lipids, are spatiotemporally transported to their destination within the endomembrane system. This includes the secretory transport of newly synthesized proteins to the cell surface or the outside of the cell, the endocytic transport of extracellular cargoes or plasma membrane components into the cell, and the recycling or shuttling transport of cargoes between the subcellular organelles, etc. Membrane trafficking events are crucial to the development, growth, and environmental adaptation of all eukaryotic cells and, thus, are under stringent regulation. Cell-surface receptor kinases, which perceive ligand signals from the extracellular space, undergo both secretory and endocytic transport. Commonly used approaches to study the membrane trafficking events using a plasma membrane-localized leucine-rich-repeat receptor kinase, ERL1, are described here. The approaches include plant material preparation, pharmacological treatment, and confocal imaging setup. To monitor the spatiotemporal regulation of ERL1, this study describes the co-localization analysis between ERL1 and a multi-vesicular body marker protein, RFP-Ara7, the time series analysis of these two proteins, and the z-stack analysis of ERL1-YFP treated with the membrane trafficking inhibitors brefeldin A and wortmannin.

Mitochondrial proton leak in cardiac aging.

Age-associated diseases are becoming progressively more prevalent, reflecting the increased lifespan of the world's population. However, the fundamental mechanisms of physiologic aging are poorly understood, and in particular, the molecular pathways that mediate cardiac aging and its associated dysfunction are unclear. Here, we focus on certain ion flux abnormalities of the mitochondria that may contribute to cardiac aging and age-related heart failure. Using oxidative phosphorylation, mitochondria pump protons from the matrix to the intermembrane space to generate a proton gradient across the inner membrane. The protons are returned to the matrix by the ATPase complex within the membrane to generate ATP. However, a portion of protons leak back to the matrix and do not drive ATP production, and this event is called proton leak or uncoupling. Accumulating evidence suggests that mitochondrial proton leak is increased in the cardiac myocytes of aged hearts. In this mini-review, we discuss the measurement methods and major sites of mitochondrial proton leak with an emphasis on the adenine nucleotide transporter 1 (ANT1), and explore the possibility of inhibiting augmented mitochondrial proton leak as a therapeutic intervention to mitigate cardiac aging.

[Association of genomic instability of CDH1 gene with clinicopathological characteristics of gastric cancer].

OBJECTIVE: To assess the association of genomic instability of epithelial cadherin 1 (CDH1) gene and clinicopathological characteristics of gastric cancer. METHODS: In total 120 paraffin-embedded gastric cancer tissue specimen were prepared, and genomic DNA was extracted. The genomic instability of the CDH1 gene was analyzed by immunohistochemistry and silver staining PCR-single-strand conformation polymorphism. RESULTS: The number of information individuals (heterozygotes) was 98 for the D16S752 locus. The detection rates for microsatellite instability (MSI) and loss of heterozygosity (LOH) at the D16S752 locus and the positive rate of CDH1 protein were 19.39%, 16.33% and 51.02%, respectively. The detection rate of MSI in TNM stages I or II was significantly higher than that in stages III or IV (P<0.05) while the detection rate of LOH was significantly lower than that in stages III or IV (P<0.05). The positive rate of CDH1 protein in TNM stages III or IV was significantly lower than that in stages I or II (P<0.05). The detection rate of MSI of cases with lymph node metastasis was significantly lower than that of without lymph node metastasis (P<0.05) while the detection rate of LOH was significantly higher than that without lymph node metastasis (P<0.05). The positive rate of CDH1 protein in patients with lymph node metastasis was significantly lower than that in patients without lymph node metastasis (P<0.05). The positive rate of CDH1 protein in MSI-positive group was significantly higher than that in MSI-negative group (P<0.05), and the positive rate of CDH1 protein in the LOH-positive group was significantly lower than that the LOH-negative group (P<0.05). CONCLUSION: The genomic instability of the CDH1 gene is associated with the progression of gastric cancer. MSI at the D16S752 locus may be used as a molecular marker for early gastric cancer, while LOH at this locus mostly occurs in advanced gastric cancer and can be regarded as an effective indicators for malignancy evaluation and prognosis.

Rifaximin protects against circadian rhythm disruption-induced cognitive impairment through preventing gut barrier damage and neuroinflammation.

Circadian rhythm disruption (CRD) is a potential risk factor for developing Alzheimer's disease (AD). However, the mechanistic link between CRD and AD is still not fully understood. CRD may lead to intestinal barrier impairment. Several studies in animals and humans suggest a connection between gut microbiota disturbance, intestinal barrier damage and neurodegenerative diseases. In this study, we investigated the effect of CRD on cognition in mice and explored the role of intestinal barrier and inflammatory responses in this process. CRD modulates the composition of gut microbiota, impairs intestinal barrier integrity, and induces both peripheral and central inflammation and cognitive impairment in mice. Rifaximin, a non-absorbable antibiotic which modulates the gut microbial composition and increases intestinal barrier integrity, effectively suppresses inflammatory responses, and rescues cognitive impairment induced by CRD. Furthermore, the impairment in hippocampal neurogenesis, tau hyperphosphorylation, and loss in synaptic proteins in CRD mice is also reversed by Rifaximin. These data identify that the impaired intestinal barrier integrity related to gut microbiota disturbance plays a key role in CRD-induced inflammatory responses and cognitive impairments in mice, and Rifaximin is effective in preventing CRD-induced cognitive deficit through protecting the gut barrier and ameliorating neuroinflammation.

Surgery offers survival advantage over radiotherapy in patients who are 80 years and older with Stage I and II NSCLC: A retrospective cohort study of 7,045 patients.

Objective: Elderly people are less likely than younger patients to undergo curative surgery for early-stage lung cancer because of the greater risk of surgery and postoperative complications. We investigated the relationship between treatment modality and the risk of all-cause and lung cancer-specific mortality to compare the efficacy of surgical treatment with radiotherapy in patients with stage I and II non-small cell lung cancer (NSCLC) who were ≥80 years old. Methods: We extracted data from the most recent Surveillance, Epidemiology, and End Results 9 registry study database (2010-2017). We mainly selected patients with stage I and II NSCLC who were ≥80 years old, and after screening, 7,045 cases were selected for our study. We used univariate analysis, stratified analysis, and multiple regression equation analysis to examine all-cause mortality and lung cancer-specific mortality in different treatment modalities. The overall and stratified populations' survival curves were plotted using the Kaplan-Meier method. The competing risk regression method of Fine and Gray was used to estimate mortality specific to lung cancer. Results: In the fully adjusted model, all-cause mortality was 1.97 times higher in the radiotherapy-only group (hazard ration (HR) = 1.97, 95% confidence interval (CI) = 1.81-2.14, p < 0.0001) than in the surgery-only group. The lung cancer-specific mortality rate was 1.22 times higher in the radiotherapy-only group (HR = 1.22, 95% CI = 1.13-1.32, p < 0.0001) than in the surgery-only group. The median overall survival (OS) in the surgery-only, radiation therapy-only, surgery plus radiation therapy, and no-treatment groups were 58 months, 31 months, 36 months, and 10 months, respectively. Median lung cancer-specific survival was 61 months, 32 months, 38 months, and 11 months, respectively. The surgery-only group had the highest 1-year OS (0.8679,95% CI = 0.8537-0.8824) and 5-year OS (0.4873, 95% CI = 0.4632-0.5126). Conclusions: Surgery had a higher overall and lung cancer-specific survival rate than radiotherapy and no treatment in the elderly early-stage NSCLC population. For patients with stage I and stage II NSCLC at advanced ages, surgical treatment might have a greater potential survival benefit.

CIP2A deficiency promotes depression-like behaviors in mice through inhibition of dendritic arborization.

Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization.

Protocol for Isolation of Cardiomyocyte from Adult Mouse and Rat.

The isolation of intact single adult cardiomyocytes from model animals, mouse and rat, is an essential tool for cardiac molecular and cellular research. While several methods are reported for adult mouse cardiomyocyte isolation, the viability and yield of the isolated cells have been variable. Here, we describe step-by-step protocols for high viability and yield cardiomyocyte isolation from mouse and rat, based on the use of a stable pressure Langendorff perfusion system. After the animal is euthanized or terminally anesthetized, the heart is removed from the chest and subject to Langendorff perfusion. Then, the heart is digested by perfusion with collagenase and hyaluronidase. After thorough digestion, the cardiomyocytes are dispersed and gradually recovered, the extracellular Ca2+ concentration adjusted, and cells are then ready for use. This protocol will facilitate research that requires isolated adult mouse and rat cardiomyocytes.

Zinc in Regulating Protein Kinases and Phosphatases in Neurodegenerative Diseases.

Zinc is essential for human growth and development. As a trace nutrient, zinc plays important roles in numerous signal transduction pathways involved in distinct physiologic or pathologic processes. Protein phosphorylation is a posttranslational modification which regulates protein activity, degradation, and interaction with other molecules. Protein kinases (PKs) and phosphatases (PPs), with their effects of adding phosphate to or removing phosphate from certain substrates, are master regulators in controlling the phosphorylation of proteins. In this review, we summarize the disturbance of zinc homeostasis and role of zinc disturbance in regulating protein kinases and protein phosphatases in neurodegenerative diseases, with the focus of that in Alzheimer's disease, providing a new perspective for understanding the mechanisms of these neurologic diseases.

In-situ reaction compatibilization modification of poly(butylene succinate-co-terephthalate)/polylactide acid blend films by multifunctional epoxy compound.

Poly(butylene succinate-co-terephthalate) (PBST) copolyester, is a new type of biodegradable synthetic polymer material that has emerged in recent years, but it cannot meet the market requirements, because of its low strength. The high-strength and high-modulus polylactic acid (PLA) was blended with PBST to increase its strength, and the chain extender ADR-4370 was used to modify PBST/PLA films by reaction and compatibilization. Compared with the 80/20 wt% PBST/PLA films, the tensile strength after modification with 0.3 wt% ADR was increased by 21.8 % and 44.3 % in the machine direction (MD) and in the transverse direction (TD), respectively. The Water Vapor Permeability (WVP) was decreased from 10.0 × 10-14 to 3.09 × 10-14 g·cm/cm2·s·Pa. The compatibilization mechanism was studied by gel permeation chromatography, infrared spectroscopy, dynamic mechanical analysis, rheological analysis, and other characterization methods. The formation of the copolymer PLA-g-PBST is the most important factor to improve the compatibility of the system and the mechanical properties of the films.

Artificial Intelligence for Screening of Multiple Retinal and Optic Nerve Diseases.

Importance: The lack of experienced ophthalmologists limits the early diagnosis of retinal diseases. Artificial intelligence can be an efficient real-time way for screening retinal diseases. Objective: To develop and prospectively validate a deep learning (DL) algorithm that, based on ocular fundus images, recognizes numerous retinal diseases simultaneously in clinical practice. Design, Setting, and Participants: This multicenter, diagnostic study at 65 public medical screening centers and hospitals in 19 Chinese provinces included individuals attending annual routine medical examinations and participants of population-based and community-based studies. Exposures: Based on 120 002 ocular fundus photographs, the Retinal Artificial Intelligence Diagnosis System (RAIDS) was developed to identify 10 retinal diseases. RAIDS was validated in a prospective collected data set, and the performance between RAIDS and ophthalmologists was compared in the data sets of the population-based Beijing Eye Study and the community-based Kailuan Eye Study. Main Outcomes and Measures: The performance of each classifier included sensitivity, specificity, accuracy, F1 score, and Cohen κ score. Results: In the prospective validation data set of 208 758 images collected from 110 784 individuals (median [range] age, 42 [8-87] years; 115 443 [55.3%] female), RAIDS achieved a sensitivity of 89.8% (95% CI, 89.5%-90.1%) to detect any of 10 retinal diseases. RAIDS differentiated 10 retinal diseases with accuracies ranging from 95.3% to 99.9%, without marked differences between medical screening centers and geographical regions in China. Compared with retinal specialists, RAIDS achieved a higher sensitivity for detection of any retinal abnormality (RAIDS, 91.7% [95% CI, 90.6%-92.8%]; certified ophthalmologists, 83.7% [95% CI, 82.1%-85.1%]; junior retinal specialists, 86.4% [95% CI, 84.9%-87.7%]; and senior retinal specialists, 88.5% [95% CI, 87.1%-89.8%]). RAIDS reached a superior or similar diagnostic sensitivity compared with senior retinal specialists in the detection of 7 of 10 retinal diseases (ie, referral diabetic retinopathy, referral possible glaucoma, macular hole, epiretinal macular membrane, hypertensive retinopathy, myelinated fibers, and retinitis pigmentosa). It achieved a performance comparable with the performance by certified ophthalmologists in 2 diseases (ie, age-related macular degeneration and retinal vein occlusion). Compared with ophthalmologists, RAIDS needed 96% to 97% less time for the image assessment. Conclusions and Relevance: In this diagnostic study, the DL system was associated with accurately distinguishing 10 retinal diseases in real time. This technology may help overcome the lack of experienced ophthalmologists in underdeveloped areas.

Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment.

We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs elamipretide (SS-31) and nicotinamide mononucleotide (NMN) to reverse aging-associated changes in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are altered with age, while also inducing additional changes. Age-related increases in protein acetylation were predominantly in mitochondrial pathways such as mitochondrial dysfunction, oxidative phosphorylation, and TCA cycle signaling. We further assessed how these age-related changes associated with diastolic function (Ea/Aa) and systolic function (fractional shortening under higher workload) measurements from echocardiography. These results identify a subset of protein abundance and acetylation changes in muscle, mitochondrial, and structural proteins that appear to be essential in regulating diastolic function in old hearts.

Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling.

Alzheimer's disease (AD) is the most common neurodegenerative disease with limited therapeutic strategies. Cell cycle checkpoint protein kinase 1 (Chk1) is a Ser/Thr protein kinase which is activated in response to DNA damage, the latter which is an early event in AD. However, whether DNA damage-induced Chk1 activation participates in the development of AD and Chk1 inhibition ameliorates AD-like pathogenesis remain unclarified. Here, we demonstrate that Chk1 activity and the levels of protein phosphatase 2A (PP2A) inhibitory protein CIP2A are elevated in AD human brains, APP/PS1 transgenic mice, and primary neurons with Aß treatment. Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Moreover, Chk1 inhibitor (GDC0575) effectively increases PP2A activity, decreases tau phosphorylation, and inhibits Aß overproduction in AD cell models. GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer's disease and highlights the therapeutic potential of Chk1 inhibitors in AD.