Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss.

BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. RESULTS: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. CONCLUSION: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

Bibliometric analysis of the global research status and trends of mechanotransduction in cancer.

BACKGROUND: The development of cancer is thought to involve the dynamic crosstalk between the tumor cells and the microenvironment they inhabit. Such crosstalk is thought to involve mechanotransduction, a process whereby the cells sense mechanical cues such as stiffness, and translate these into biochemical signals, which have an impact on the subsequent cellular activities. Bibliometric analysis is a statistical method that involves investigating different aspects (including authors' names and affiliations, article keywords, journals and citations) of large volumes of literature. Despite an increase in mechanotransduction-related research in recent years, there are currently no bibliometric studies that describe the global status and trends of mechanotransduction-related research in the cancer field. AIM: To investigate the global research status and trends of mechanotransduction in cancer from a bibliometric viewpoint. METHODS: Literature on mechanotransduction in cancer published from January 1, 1900 to December 31, 2022 was retrieved from the Web of Science Core Collection. Excel and GraphPad software carried out the statistical analysis of the relevant author, journal, organization, and country information. The co-authorship, keyword co-occurrence, and keyword burst analysis were visualized with VOSviewer and CiteSpace. RESULTS: Of 597 publications from 745 institutions in 45 countries were published in 268 journals with 35510 citation times. With 270 articles, the United States is a well-established global leader in this field, and the University of California system, the most productive (n = 36) and influential institution (n = 4705 citations), is the most highly active in collaborating with other organizations. Cancers was the most frequent publisher with the highest H-index. The most productive researcher was Valerie M. Weaver, with 10 publications. The combined analysis of concurrent and burst keywords revealed that the future research hotspots of mechanotransduction in cancer were related to the plasma membrane, autophagy, piezo1/2, heterogeneity, cancer diagnosis, and post-transcriptional modifications. CONCLUSION: Mechanotransduction-related cancer research remains a hot topic. The United States is in the leading position of global research on mechano-oncology after almost 30 years of investigations. Research group cooperations exist but remain largely domestic, lacking cross-national communications. The next big topic in this field is to explore how the plasma membrane and its localized mechanosensor can transduce mechanical force through post-transcriptional modifications and thereby participate in cellular activity regulations and cancer development.

Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.

BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H+-ATPase (v-ATPase) activity, respectively, which were analysed by One-way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One-way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC). RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.

Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion.

PARP1 and Chk1 inhibitors have been shown to be synergistic in different cancer models in relatively short time treatment modes. However, the consequences of long-term/repeated treatments with the combinations in cancer models remain unclear. In this study, the synergistic cytotoxicity of their combinations in 8 tumor cell lines was confirmed in a 7-day exposure mode. Then, pancreatic Capan-1 cells were repeatedly treated with the PARP1 inhibitor olaparib, the Chk1 inhibitor rabusertib or their combination for 211-214 days, during which the changes in drug sensitivity were monitored at a 35-day interval. Unexpectedly, among the 3 treatment modes, the combination treatments resulted in the highest-grade resistance to Chk1 (~14.6 fold) and PARP1 (~420.2 fold) inhibitors, respectively. Consistently, G2/M arrest and apoptosis decreased significantly in the resulting resistant variants exposed to olaparib. All 3 resistant variants also unexpectedly obtained enhanced migratory and invasive capabilities. Moreover, the combination treatments resulted in increased migration and invasion than olaparib alone. The expression of 124 genes changed significantly in all the resistant variants. We further demonstrate that activating CXCL3-ERK1/2 signaling might contribute to the enhanced migratory capabilities rather than the acquired drug resistance. Our findings indicate that repeated treatments with the rabusertib/olaparib combination result in increased drug resistance and a more aggressive cell phenotype than those with either single agent, providing new clues for future clinical anticancer tests of PARP1 and Chk1 inhibitor combinations.

Accuro ultrasound-based system with computer-aided image interpretation compared to traditional palpation technique for neuraxial anesthesia placement in obese parturients undergoing cesarean delivery: a randomized controlled trial.

PURPOSE: Recently, a new handheld ultrasound-based device, called Accuro, has been commercialized with a real-time automated interpretation of lumbar ultrasound images. We hypothesized that the handheld ultrasound device would improve the efficacy and safety of combined spinal-epidural anesthesia (CSEA) for cesarean delivery in obese parturients. METHODS: Eighty parturients with a body mass index > 30 kg∙m-2 scheduled for elective cesarean delivery were randomly allocated equally (palpation group and ultrasound group). The primary outcome was the first insertion success rate. Secondary outcomes were the time taken to identify the needle puncture site, duration of CSEA procedure, the total time, the rate of parturients who require needle redirections, the number of skin punctures, changes in the intended interspace, and the incidence of complications. RESULTS: Compared to the palpation group, the first insertion success rate was significantly higher (72.5% vs. 40.0%; P = 0.003), and time taken to identify the needle puncture site was less (30 [26-36] vs. 39 [32-49] seconds; P = 0.001) in the ultrasound group. The rate of parturients who required needle redirections (40.0% vs. 72.5%; P = 0.003) and the incidence of paresthesia were both lower (7.5% vs. 45.0%; P < 0.001). The other outcomes had no significant difference between groups. The mean difference between the epidural depth measured by the handheld ultrasound and needle depth was - 0.29 cm [95% limit of agreement, - 0.52 to - 0.05]. CONCLUSIONS: Our study suggests using the Accuro ultrasound device can enhance the efficacy and safety of CSEA in obese parturients when executed by experienced anesthesiologists, and its automated estimation of epidural depth is accurate.

Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers.

G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.

Glycogen synthase kinase 3ß inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.

Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3ß and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3ß was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3ß could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

Gene diagnosis of infantile neurofibromatosis type I: A case report.

BACKGROUND: Neurofibromatosis is an autosomal dominant genetic disorder with various manifestations. Systemic multiple neurofibromatosis is rare in infancy. The disease is difficult to identify in the early stage, and it is prone to misdiagnosis and missed diagnosis. In the presence of lower limb swelling with subcutaneous nodules of unknown cause, café-au-lait spots, and axillary freckles, this disease must be considered. This report presents the clinical manifestations, early detection, diagnosis and treatment, and prognosis of infantile neurofibromatosis type I (NF1). CASE SUMMARY: The clinical manifestations, imaging examinations, and gene results of a 3-mo-old male infant with NF1 were analyzed retrospectively. He had "swelling of both legs" at the onset and developed café-au-lait spots, axillary freckles, and multiple neurofibromas later. He had a family history of similar conditions. Gene detection showed a heterozygous mutation of c.4537C>T in the NF1 gene, leading to a nonsense mutation of amino acids (p.R1513x), which originated from the mother of the infant. He was diagnosed with NF1. CONCLUSION: Gene diagnosis plays an important role in the early diagnosis of NF1.

Morin exerts protective effects on encephalopathy and sepsis-associated cognitive functions in a murine sepsis model.

Sepsis-associated encephalopathy (SAE) often leads to cognitive impairments in the rest life of septic survivors. The potential pathological changes of SAE are complicated and have not been fully understood. Morin, a flavone compound exhibiting neuroprotective activity and anti-inflammation effect, was employed to treat with CLP-induced septic mice in our study. The data from a novel object recognition test and tail suspension test indicated that morin treatment reversed cognitive dysfunction and relieved depressive-like behaviors in septic mice. Morin down-regulated the expressions of IL-6, MCP-1, TNF-α and IL-10 in serum and diminished microglia activation in septic mice. Additionally, Western blot results showed that morin reduced the phosphokinase GSK3ß activity and elevated the phosphatase PP2A activity, which led to lower tau phosphorylation. Morin reduced Aß deposition and protected the synapse integrity, which might be the possible mechanism of protecting cognitive functions in septic mice. In conclusion, we identified that morin exerted anti-inflammation and anti-neurodegeneration effects in septic mice, and prevented further cognitive impairments.

Structuring Hierarchically Porous Architecture in Biomass-Derived Carbon Aerogels for Simultaneously Achieving High Electromagnetic Interference Shielding Effectiveness and High Absorption Coefficient.

Developing high-performance electromagnetic interference (EMI) shielding materials with high absorption coefficient is highly desired for eliminating the secondary pollution of reflected electromagnetic wave (EMW). Nevertheless, it has long been a daunting challenge to achieve high shielding effectiveness (SE) and ultralow or no reflection SE simultaneously. Herein, highly porous and conductive carbon nanotube (CNT)-based carbon aerogel with a meticulously designed hierarchically porous structure from micro and sub-micro to nano levels is developed by specific two-stage pyrolysis and potassium hydroxide activation processes. The resultant activated cellulose-derived carbon aerogels (a-CCAs) exhibit an ultrahigh EMI SE of 96.4 dB in the frequency range of 8.2-12.4 GHz in conjunction with an exceptionally high absorption coefficient of 0.79 at a low density of 30.5 mg cm-3. The successful construction of hierarchically porous structure is responsible for the excellent "structurally absorbing" ability of a-CCAs, and the introduction of CNT-based heterogeneous conductive network can effectively dissipate the incident EMWs by interfacial polarization and microcurrent losses. Moreover, the as-prepared a-CCAs have a water contact angle of as high as 158.3°and a sliding angle of as low as 5.3°, revealing their superhydrophobic feature. The ingenious structure design proposed here provides a possible pathway to overcome the conflict between high EMI shielding performance and ultralow or no secondary reflection, and the as-prepared a-CCAs are exceedingly promising in the application of telecommunication, microelectronics, and spacecraft.

The Development of the Chinese Sentiment Lexicon for Internet.

This paper examines the development of the Chinese Sentiment Lexicon for Internet (CSLI), a sentiment lexicon for capturing the valence and arousal in Chinese online social media texts. We first review the current sentiment lexicons and their building process, including the collection of words, judging the emotionality of words, and testing reliability and validity. In Study 1, we develop CSLI and test its initial reliability and validity. In Study 2, we further test the convergent validity of CSLI by examining its correlations with human judgment in 429 aggregated Weibo comments. In Study 3, the predictive validity of CSLI is examined by linking its results to personality traits among 52 undergraduates. Two replication studies are also conducted to verify the findings in Study 2 and 3. The results have generally supported the reliability and validity of CSLI. Therefore, CSLI can be used as a research tool to capture the degree of valence and arousal in Chinese online social media texts. Its potential to promote human well-being is also discussed.

Microglia CREB-Phosphorylation Mediates Amyloid-ß-Induced Neuronal Toxicity.

Extracellular accumulation of amyloid-ß (Aß) forming senile plaques is one of the hallmark pathologies in Alzheimer's disease (AD), while the mechanisms underlying the neuronal toxic effect of Aß are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aß42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aß infusion. Aß treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aß-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aß-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aß only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation.

Robust carbon nanotube foam for efficient electromagnetic interference shielding and microwave absorption.

Lightweight and robust carbon nanotube (CNT)/chitosan (CS) foams were assembled by a facile unidirectional freeze-drying method in this work. The CNT/CS foam exhibited an excellent electromagnetic interference (EMI) shielding effectiveness (SE) of 37.6 dB while the density was only 17.6 mg·cm-3, and thus the corresponding specific SE was up to 8556 dB·cm2·g-1. The superior EMI shielding performance was mainly attributed to the perfect conductive networks. Additionally, the absorption coefficient of CNT/CS foam was up to 81.73% under high EMI SE of 37.6 dB, which was remarkable among the reported EMI shielding materials with comparable EMI shielding level. More importantly, the addition of CS significantly increased the compressive strength and modulus of CNT/CS foam to 34.1 KPa and 177.1 KPa, which were 84% and 149% higher than those for the pure CNT foam, respectively. These results indicate that the CNT/CS foam is an ideal high-efficient EMI shielding material, which has high potential applications in the fields of aerospace, automotive, and electronic devices.

Role of exosome-associated microRNA in diagnostic and therapeutic applications to metabolic disorders.

Metabolic disorders are classified clinically as a complex and varied group of diseases including metabolic syndrome, obesity, and diabetes mellitus. Fat toxicity, chronic inflammation, and oxidative stress, which may change cellular functions, are considered to play an essential role in the pathogenetic progress of metabolic disorders. Recent studies have found that cells secrete nanoscale vesicles containing proteins, lipids, nucleic acids, and membrane receptors, which mediate signal transduction and material transport to neighboring and distant cells. Exosomes, one type of such vesicles, are reported to participate in multiple pathological processes including tumor metastasis, atherosclerosis, chronic inflammation, and insulin resistance. Research on exosomes has focused mainly on the proteins they contain, but recently the function of exosome-associated microRNA has drawn a lot of attention. Exosome-associated microRNAs regulate the physiological function and pathological processes of metabolic disorders. They may also be useful as novel diagnostics and therapeutics given their special features of non-immunogenicity and quick extraction. In this paper, we summarize the structure, content, and functions of exosomes and the potential diagnostic and therapeutic applications of exosome-associated microRNAs in the treatment of metabolic disorders.

Deletion of Type-2 Cannabinoid Receptor Induces Alzheimer's Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3ß Pathway.

Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer's disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R-/- mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R-/- mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3ß activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R-/- mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3ß activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3ß disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3ß pathway. These findings proved that CB2R/AMPK/GSK3ß pathway can be a promising new drug target for AD.

Biomarkers for Early Diagnostic of Mild Cognitive Impairment in Type-2 Diabetes Patients: A Multicentre, Retrospective, Nested Case-Control Study.

BACKGROUND: Both type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are common age-associated disorders and T2DM patients show an increased risk to suffer from AD, however, there is currently no marker to identify who in T2DM populations will develop AD. Since glycogen synthase kinase-3ß (GSK-3ß) activity, ApoE genotypes and olfactory function are involved in both T2DM and AD pathogenesis, we investigate whether alterations of these factors can identify cognitive impairment in T2DM patients. METHODS: The cognitive ability was evaluated using Minimum Mental State Examination (MMSE) and Clinical Dementia Rating (CDR), and the mild cognitive impairment (MCI) was diagnosed by Petersen's criteria. GSK-3ß activity in platelet, ApoE genotypes in leucocytes and the olfactory function were detected by Western/dot blotting, the amplification refractory mutation system (ARMS) PCR and the Connecticut Chemosensory Clinical Research Center (CCCRC) test, respectively. The odds ratio (OR) and 95% confidence intervals (95% CI) of the biomarkers for MCI diagnosis were calculated by logistic regression. The diagnostic capability of the biomarkers was evaluated by receiver operating characteristics (ROC) analyses. FINDINGS: We recruited 694 T2DM patients from Jan. 2012 to May. 2015 in 5 hospitals (Wuhan), and 646 of them met the inclusion criteria and were included in this study. 345 patients in 2 hospitals were assigned to the training set, and 301 patients in another 3 hospitals assigned to the validation set. Patients in each set were randomly divided into two groups: T2DM without MCI (termed T2DM-nMCI) or with MCI (termed T2DM-MCI). There were no significant differences for sex, T2DM years, hypertension, hyperlipidemia, coronary disease, complications, insulin treatment, HbA1c, ApoE ε2, ApoE ε3, tGSK3ß and pS9GSK3ß between the two groups. Compared with the T2DM-nMCI group, T2DM-MCI group showed lower MMSE score with older age, ApoE ε4 allele, higher olfactory score and higher rGSK-3ß (ratio of total GSK-3ß to Ser9-phosphorylated GSK-3ß) in the training set and the validation set. The OR values of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 1.09, 2.09, 1.51, 10.08 in the training set, and 1.06, 2.67, 1.47, 7.19 in the validation set, respectively. The diagnostic accuracy of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 0.76, 0.72, 0.66, 0.79 in the training set, and 0.70, 0.68, 0.73, 0.79 in the validation set, respectively. These four combined biomarkers had the area under the curve (AUC) of 82% and 86%, diagnostic accuracy of 83% and 81% in the training set and the validation set, respectively. INTERPRETATION: Aging, activation of peripheral circulating GSK-3ß, expression of ApoE ε4 and increase of olfactory score are diagnostic for the mild cognitive impairment in T2DM patients, and combination of these biomarkers can improve the diagnostic accuracy.

Magnesium protects cognitive functions and synaptic plasticity in streptozotocin-induced sporadic Alzheimer's model.

Alzheimer's disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3ß at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3ß in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.