Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

Aging gene signature of IL-7 receptor alpha low effector memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

CD45RA+ effector memory (EM) CD8+ T cell expansion was reported in Alzheimer's disease (AD). Such cells are IL-7 receptor alpha (IL-7Rα)low EM CD8+ T cells, which expand with age and have a unique aging gene signature (i.e., IL-7Rαlow aging genes). Here we investigated whether IL-7Rαlow aging genes and previously reported AD and memory (ADM) genes overlapped with clinical significance in AD patients. RT-qPCR analysis of 40 genes, including 29 ADM, 9 top IL-7Ralow aging and 2 control genes, showed 8 differentially expressed genes between AD and cognitively normal groups; five (62.5%) of which were top IL-7Rαlow aging genes. Over-representation analysis revealed that these genes were highly present in molecular and biological pathways associated with AD. Distinct expression levels of these genes were associated with neuropsychological testing performance in 3 subgroups of dementia participants. Our findings support the possible implication of the IL-7Rαlow aging gene signature with AD.

Translationally controlled tumor protein restores impaired memory and altered synaptic protein expression in animal models of dementia.

This study describes the effects of translationally controlled tumor protein (TCTP) on mice with memory impairment caused by scopolamine (SCO) administration. Specifically, memory functions and expression levels of hippocampal synaptic proteins in 7- to 12-month-old SCO-treated wild-type (WT-SCO) mice were compared to those of TCTP-overexpressing (TG) and TCTP knocked-down (KD) mice similarly treated with SCO. Passive-avoidance tasks were performed with WT, TG, and KD mice for four weeks after intraperitoneal injection of SCO or saline followed by an acquisition test. After completing behavioral studies, hippocampi of all mice groups were collected and their synaptic protein contents were subjected to Western blotting or immunohistochemical analyses, and compared with those of 5x familial Alzheimer's disease (5xFAD) mice and postmortem AD patients. Results of passive avoidance tests revealed that SCO-induced memory impairment was repaired in TCTP-TG mice, but not in TCTP-KD mice. Hippocampal expression levels of synaptophysin, synapsin-1, and PSD-95 were increased in TCTP-TG mice treated with SCO (TG-SCO) but decreased in TCTP-KD mice treated with SCO (KD-SCO). Decreased levels of TCTP, synaptophysin, and PSD-95 were also found in hippocampi of 5xFAD mice and AD patients. Expression levels of p-CREB/CREB and brain-derived neurotrophic factor (BDNF) in TCTP-TG and TG-SCO mice were similar to or increased compared to those in WT mice, but decreased in TCTP-KD and KD-SCO mice. BDNF immunoreactivity was restored in CA1 regions of hippocampi of TG-SCO mice, but not in KD-SCO mice. These results suggest that TCTP can restore damaged memory in mice possibly through restored synaptic protein expression.

Effect of radiofrequency exposure on body temperature: Real-time monitoring in normal rats.

Radiofrequency radiation (RFR) can generate heat in living organisms. In this study, we monitored the body temperature of healthy animals during RFR exposure in real time using an implantable iButton data logger. A reverberation chamber system for small animals was used for this radiofrequency (RF) exposure in vivo study. Healthy male Sprague-Dawley rats were divided into two groups: with versus without iButton implantation (n = 20 per group). Each group was further divided into a sham-exposed and RF-exposed group (n = 10 per subgroup). Rats were exposed to a 1,760-MHz long-term evolution (LTE) signal in the reverberation chamber system at a whole-body average specific absorption rate of 0 W/kg (sham-exposed) or 4 W/kg (RF-exposed) for 6 h. The body temperature of iButton-implanted rats was recorded using an intraperitoneally implanted iButton every minute over 6 h of RF exposure, whereas that of non-implanted rats was measured directly using a rectal thermometer immediately before and after the 6-h RF exposure period. The temperature values measured by the two types of thermometers were significantly positively correlated (r = 0.63, P < 0.01, linear regression), and changes in body temperatures recorded in iButton-implanted and non-implanted rats measured using two thermometers after 6 h of RF exposure were maintained within <1°C (P = 0.87, general linear model, followed by univariate model). Similar results were obtained for rectal thermometer measurements (P = 0.12, paired t-test). These results suggest that RF exposure at a whole-body average specific absorption rate of 4 W/kg does not induce significant changes in body temperature in healthy rats over a 6-h RF exposure period.

Striatal ZBTB16 Is Associated With Cognitive Deficits in Alzheimer Disease Mice.

PURPOSE: In Alzheimer disease (AD), brain regions such as the cortex and the hippocampus show abundant amyloid load which correlates with cognitive function decline. Prior to the significant development of AD pathophysiology, patients report the manifestation of neuropsychiatric symptoms, indicating a functional interplay between basal ganglia structures and hippocampal regions. Zinc finger and BTB domain-containing protein 16 (ZBTB16) is a transcription factor that controls the expression of downstream genes and the involvement of ZBTB16 in the striatum undergoing pathological aging in AD and the resulting behavioral phenotypes has not yet been explored. METHODS: To study molecular alterations in AD pathogenesis, we analyzed the brain from amyloid precursor protein (APP)/ presenilin 1 (PS1) transgenic mice. The molecular changes in the striatal region of the brain were analyzed via the immunoblotting, and the quantitative RNA sequencing. The cognitive impairments of APP/PS1 mice were assessed via 3 behavioral tests: 3-chamber test, Y-maze test, and noble object recognition test. And multielectrode array experiments for the analysis of the neuronal activity of the striatum in APP/PS1 mice was performed. RESULTS: We found that the alteration in ZBTB16 levels that occurred in the early ages of the pathologically aging striatum coalesces with the disruption of transcriptional dysregulation while causing social memory deficits, anxiety-like behavior. The early ZBTB16 knockdown treatment in the striatum of APP/PS1 mice rescued cognition that continued into later age. CONCLUSION: This study demonstrates that perturbation of transcriptional regulation of ZBTB16 during pathological aging may influence cognitive impairments and reveals a potent approach to targeting the transcriptional regulation of the striatum for the treatment of AD.

Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice, an AD model.

BACKGROUND: Aducanumab (Adu), which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid, has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose (10 mg/kg) of the drug in Alzheimer's disease (AD) clinical trials. The purpose of this study was to investigate the effects of a lower dose of Adu (3 mg/kg) with enhanced delivery via focused ultrasound (FUS) in an AD mouse model. METHODS: The FUS with microbubbles opened the blood-brain barrier (BBB) of the hippocampus for the delivery of Adu. The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly. Y-maze test, Brdu labeling, and immunohistochemical experimental methods were employed in this study. In addition, RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals. RESULTS: The FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains. The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone. Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice. Furthermore, RNA sequencing identified that 4 enriched canonical pathways including phagosome formation, neuroinflammation signaling, CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment. CONCLUSION: In conclusion, the enhanced delivery of a low dose of Adu (3 mg/kg) via FUS decreases amyloid deposits and attenuates cognitive function deficits. FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery. We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.

Transcriptomic analysis in the striatum reveals the involvement of Nurr1 in the social behavior of prenatally valproic acid-exposed male mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that exhibits neurobehavioral deficits characterized by abnormalities in social interactions, deficits in communication as well as restricted interests, and repetitive behaviors. The basal ganglia is one of the brain regions implicated as dysfunctional in ASD. In particular, the defects in corticostriatal function have been reported to be involved in the pathogenesis of ASD. Surface deformation of the striatum in the brains of patients with ASD and their correlation with behavioral symptoms was reported in magnetic resonance imaging (MRI) studies. We demonstrated that prenatal valproic acid (VPA) exposure induced synaptic and molecular changes and decreased neuronal activity in the striatum. Using RNA sequencing (RNA-Seq), we analyzed transcriptome alterations in striatal tissues from 10-week-old prenatally VPA-exposed BALB/c male mice. Among the upregulated genes, Nurr1 was significantly upregulated in striatal tissues from prenatally VPA-exposed mice. Viral knockdown of Nurr1 by shRNA significantly rescued the reduction in dendritic spine density and the number of mature dendritic spines in the striatum and markedly improved social deficits in prenatally VPA-exposed mice. In addition, treatment with amodiaquine, which is a known ligand for Nurr1, mimicked the social deficits and synaptic abnormalities in saline-exposed mice as observed in prenatally VPA-exposed mice. Furthermore, PatDp+/- mice, a commonly used ASD genetic mouse model, also showed increased levels of Nurr1 in the striatum. Taken together, these results suggest that the increase in Nurr1 expression in the striatum is a mechanism related to the changes in synaptic deficits and behavioral phenotypes of the VPA-induced ASD mouse model.

An International Collaborative Animal Study of the Carcinogenicity of Mobile Phone Radiofrequency Radiation: Considerations for Preparation of a Global Project.

Radiofrequency radiation (RFR) was classified as a "possible" human carcinogen in 2011, which caused great public concern. A carcinogenicity study by the National Toxicology Program (NTP) found Code Division Multiple Access-and Global System for Mobile Communications-modulated mobile phone RFR to be carcinogenic to the brain and heart of male rats. As part of an investigation of mobile phone carcinogenesis, and to verify the NTP study results, a 5-year collaborative animal project was started in Korea and Japan in 2019. An international animal study of this type has two prerequisites: use of the same study protocol and the same RF-exposure system. This article discusses our experience in the design of this global study on radiofrequency electromagnetic fields (RF-EMFs).© 2022 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.

Dysfunction of striatal MeCP2 is associated with cognitive decline in a mouse model of Alzheimer's disease.

Rationale: Cerebral Methyl-CpG binding Protein 2 (MeCP2) is involved in several psychiatric disorders that are concomitant with cognitive dysfunction. However, the regulatory function of striatal MeCP2 and its association with Alzheimer's disease (AD) has been largely neglected due to the absence of amyloid plaque accumulation in the striatal region until the later stages of AD progression. Considerable evidence indicates that neuropsychiatric symptoms related to cognitive decline are involved with striatal dysfunction. To this respect, we investigated the epigenetic function of striatal MeCP2 paralleling the pathogenesis of AD. Methods: We investigated the brain from amyloid precursor protein (APP)/presenilin1 (PS1) transgenic mice and postmortem brain samples from normal subjects and AD patients. The molecular changes in the brain, particularly in the striatal regions, were analyzed with thioflavin S staining, immunohistochemistry, immunoblotting, and MeCP2 chromatin immunoprecipitation sequencing (ChIP-seq). The cognitive function of APP/PS1 mice was assessed via three behavioral tests: 3-chamber test (3CT), Y-maze test (YMT), and passive avoidance test (PA). A multi-electrode array (MEA) was performed to analyze the neuronal activity of the striatum in APP/PS1 mice. Results: Striatal MeCP2 expression was increased in the younger (6 months) and older (10 months) ages of APP/PS1 mice, and the genome-wide occupancy of MeCP2 in the younger APP/PS1 showed dysregulated binding patterns in the striatum. Additionally, we confirmed that APP/PS1 mice showed behavioral deficits in multiple cognitive behaviors. Notably, defective cognitive phenotypes and abnormal neuronal activity in old APP/PS1 mice were rescued through the knock-down of striatal MeCP2. Conclusion: We found that the MeCP2-mediated dysregulation of the epigenome in the striatum is linked to the defects in cognitive behavior and neuronal activity in the AD animal model, and that this alteration is initiated even in the very early stages of AD pathogenesis. Together, our data indicates that MeCP2 may be a potential target for the diagnosis and treatment of AD at asymptomatic and symptomatic stages.

COVID-19 Case Surge and Telemedicine Utilization in a Tertiary Hospital in Korea.

Background:Faced with the coronavirus disease 2019 (COVID-19) pandemic, Korea has allowed telemedicine use for a limited time. This study examined whether the surge in COVID-19 cases led to increased telemedicine use and the associated factors.Methods:Data from the electronic medical records of 929,753 outpatient episodes between March 4 and September 4, 2020, in a tertiary hospital in Korea were used. A comparison group was chosen by matching, adjusting for age and sex because only a small portion (1.0%) of the sample used telemedicine. The final sample comprised 57,972 episodes. Multivariable logistic regression analyses were performed to examine the association of independent variables with the dichotomous dependent variable (i.e., telemedicine visit/in-person visit).Results:The surge in confirmed COVID-19 cases led to significantly increased telemedicine use (101-300 new cases odds ratio [OR]: 3.00; 301-500 new cases OR: 5.82; and ≥501 new cases OR: 42.18; all p < 0.0001). Telemedicine use was also statistically associated with sex (female patients OR: 2.08), age ˃19 years, distance from the hospital (Incheon, Gyeonggi, region, OR: 1.30; and other regions, OR: 4.33), and the number of days from diagnosis (3-6 months OR: 1.21; 6-12 months OR: 1.56; 12-36 months OR: 1.98; and ≥36 months OR: 2.49). Medical Aid patients (OR: 0.83) were less likely to use telemedicine than those with National Health Insurance.Conclusions:Telemedicine can be effective in delivering health services during an outbreak. Policymakers and health care organizations are encouraged to use the results of this study to tailor telemedicine to meet the needs of patients.

Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis.

Ketamine is a dissociative anesthetic and a non-competitive NMDAR antagonist. At subanesthetic dose, ketamine can relieve pain and work as a fast-acting antidepressant, but the underlying molecular mechanism remains elusive. This study aimed to investigate the mode of action underlying the effects of acute subanesthetic ketamine treatment by bioinformatics analyses of miRNAs in the medial prefrontal cortex of male C57BL/6J mice. Gene Ontology and KEGG pathway analyses of the genes putatively targeted by ketamine-responsive prefrontal miRNAs revealed that acute subanesthetic ketamine modifies ubiquitin-mediated proteolysis. Validation analysis suggested that miR-148a-3p and miR-128-3p are the main players responsible for the subanesthetic ketamine-mediated alteration of ubiquitin-mediated proteolysis through varied regulation of ubiquitin ligases E2 and E3. Collectively, our data imply that the prefrontal miRNA-dependent modulation of ubiquitin-mediated proteolysis is at least partially involved in the mode of action by acute subanesthetic ketamine treatment.

Disruption of the astrocyte-neuron interaction is responsible for the impairments in learning and memory in 5XFAD mice: an Alzheimer's disease animal model.

The morphological dynamics of astrocytes are altered in the hippocampus during memory induction. Astrocyte-neuron interactions on synapses are called tripartite synapses. These control the synaptic function in the central nervous system. Astrocytes are activated in a reactive state by STAT3 phosphorylation in 5XFAD mice, an Alzheimer's disease (AD) animal model. However, changes in astrocyte-neuron interactions in reactive or resting-state astrocytes during memory induction remain to be defined. Here, we investigated the time-dependent changes in astrocyte morphology and the number of astrocyte-neuron interactions in the hippocampus over the course of long-term memory formation in 5XFAD mice. Hippocampal-dependent long-term memory was induced using a contextual fear conditioning test in 5XFAD mice. The number of astrocytic processes increased in both wild-type and 5XFAD mice during memory formation. To assess astrocyte-neuron interactions in the hippocampal dentate gyrus, we counted the colocalization of glial fibrillary acidic protein and postsynaptic density protein 95 via immunofluorescence. Both groups revealed an increase in astrocyte-neuron interactions after memory induction. At 24 h after memory formation, the number of tripartite synapses returned to baseline levels in both groups. However, the total number of astrocyte-neuron interactions was significantly decreased in 5XFAD mice. Administration of Stattic, a STAT3 phosphorylation inhibitor, rescued the number of astrocyte-neuron interactions in 5XFAD mice. In conclusion, we suggest that a decreased number of astrocyte-neuron interactions may underlie memory impairment in the early stages of AD.

Increased expression levels of AURKA and KIFC1 are promising predictors of progression and poor survival associated with gastric cancer.

Increased cell proliferation is a critical hallmark of cancer development and progression. The proliferation of tumor cells depends on mitotic deregulation. Here, we identified the differentially expressed genes (DEGs) in gastric cancer (GC) through RNA sequencing data and bioinformatics analysis. Subsequent functional and pathway enrichment analyses showed that the screened DEGs were enriched in the mitosis-associated pathway. Based on the analysis results, we selected two signatures (aurora kinase A [AURKA] and kinesin family member C1 [KIFC1]) to determine their clinicopathological significance. The results showed a significant positive correlation between AURKA and KIFC1 expression both at the mRNA and protein levels. AURKA expression was positively correlated with distant metastases (p = 0.032) and tumor-node-metastasis (TNM) stage (p = 0.001). Elevated KIFC1 expression was significantly associated with tumor size (p = 0.029), depth of invasion (p < 0.001), lymph node metastasis (p < 0.001), distant metastasis (p = 0.023), and TNM stage (p < 0.001). Higher AURKA (hazard ratio [HR] = 1.3, p < 0.001) and KIFC1 (HR = 1.41, p < 0.001) mRNA levels were also significantly correlated with poor overall survival. Thus, AURKA and KIFC1 could serve as potential prognostic markers and therapeutic targets for GC.

Modulation of Neuroinflammation by Low-Dose Radiation Therapy in an Animal Model of Alzheimer's Disease.

PURPOSE: Recently, several studies have reported that low-dose radiation therapy (RT) suppresses the release of proinflammatory cytokines in inflammatory-degenerative disorders, including Alzheimer disease (AD). AD is the most common cause of dementia, and neuroinflammation is one of the major contributing factors in AD pathogenesis. Therefore, low-dose RT may be used clinically for treating AD. However, the appropriate doses, effects, and underlying mechanisms of RT in AD have not been determined. In this study, we aimed to determine the appropriate RT dose and schedule for AD treatment and to investigate the therapeutic effects and mechanisms of low-dose RT in AD. METHODS AND MATERIALS: We first determined the proper dose and schedule for RT in late-stage AD using 8- to 9-month-old 5x Familial AD (5xFAD) mice, a well-known animal model of AD, by comparing the effects of a low total dose with low dose per fraction (LD-LDRT, 5 × 0.6 Gy) with those of a low moderate total dose with conventional dose per fraction (LMD-CDRT, 5 × 2 Gy). RESULTS: LD-LDRT and LMD-CDRT were found to reduce the levels of the proinflammatory cytokines CD54, IL-3, CXCL9/10, and CCL2/4 in the hippocampus of 5xFAD mice. Furthermore, increased microgliosis assessed using Iba-1 and CD68 dual immunostaining was significantly reduced by LD-LDRT and LMD-CDRT in the hippocampus of 5xFAD mice. Moreover, LD-LDRT and LMD-CDRT decreased the amyloid plaque burden in the hippocampus of 5xFAD mice and attenuated their cognitive impairment; these effects persisted for 4 to 5 weeks. CONCLUSIONS: The present study showed that LD-LDRT alleviates cognitive impairments and prevents the accumulation of amyloid plaques by regulating neuroinflammation in the late stage of AD in 5xFAD mice, with an efficacy equivalent to that of LMD-CDRT. Furthermore, the findings suggest that compared with LMD-CDRT, LD-LDRT may facilitate accessible and convenient treatment in clinical trials.

α-Syntrophin alleviates ER stress to maintain protein homeostasis during myoblast differentiation.

We have previously shown evidence that α-syntrophin plays an important role in myoblast differentiation. In this study, we focused on abnormal myotube formation of the α-syntrophin knockdown C2 cell line (SNKD). The overall amount of intracellular protein and muscle-specific proteins in SNKD cells were significantly lower than those in the control. Akt-mTOR signaling, an important pathway for protein synthesis and muscle hypertrophy, was downregulated. In addition, the levels of endoplasmic reticulum (ER) stress markers increased in SNKD cells. The decrease in intracellular protein synthesis and reduction in the myotube diameter in SNKD cells were restored by 4-phenylbutyric acid, a chemical chaperone, or overexpression of α-syntrophin. These results suggest a novel role for α-syntrophin in protein homeostasis during myoblast differentiation.

Phloroglucinol attenuates oligomeric amyloid beta peptide1-42-induced astrocytic activation by reducing oxidative stress.

Astrocytes are the most abundant cell type in the central nervous system (CNS) and their major function is to maintain homeostasis of the CNS by exerting various functions. Simultaneously, reactive astrocytes are well known to be involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Reactive astrocytes, induced by amyloid beta peptide (Aß), the main component of the neuritic plaques found in AD, induce neuroinflammation, producing cytokines that lead to neuronal cell death in AD. Phloroglucinol,a polyphenol monomer and a component of phlorotannin, is found at sufficient levels in Ecklonia cava of the Laminariaceae family. Recently, several studies have reported that phloroglucinol has the ability to trap free radicals in lung fibroblasts or cancer cells. However, the effects of phloroglucinol in astrocytes have not yet been studied. Here, we found that phloroglucinol inhibits the generation of ROS induced by oligomeric Aß1-42 (oAß1-42) treatment in primary astrocytes. Futhermore, phloroglucinol was shown to ameliorate the protein expression of glial fibrillary acidic protein, a marker of reactive astrocytes, after treatment with oAß1-42. These results indicate that phloroglucinol exerts antioxidant effects in primary cultured astrocytes and attenuates the astrocytic activation induced by oAß1-42.

STAT3 activation in microglia exacerbates hippocampal neuronal apoptosis in diabetic brains.

Diabetes mellitus (DM) characterized by hyperglycemia leads to a variety of complications, including cognitive impairment or memory loss. The hippocampus is a key brain area for learning and memory and is one of the regions that is most sensitive to diabetes. However, the pathogenesis of diabetic neuronal lesion is not yet completely understood. We focused on the association of microglia activation and brain lesions in diabetes. In this study, we investigated whether and how signal transducer and activator of transcription 3 (STAT3) activation in microglia affects neuronal lesions in diabetic brains. Using a streptozotocin-induced type 1 DM model, we showed enhanced hippocampal neuronal apoptosis that was associated with increased STAT3 activation. We found that hyperglycemia increased the expression of inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6, in the diabetic hippocampus. In particular, IFN-γ induced autocrine activation of microglia, and STAT3 activation is important for this process. We also demonstrated that STAT3 activation in microglia increased tumor necrosis factor-α (TNF-α) expression; subsequently, TNF-α increased neuronal apoptosis by increasing reactive oxygen species (ROS) levels in the neuronal cells. We also took advantage of mice lacking STAT3 in microglia and demonstrated that depletion of microglial STAT3 reduced neuronal apoptosis in the diabetic hippocampus. Taken together, these results suggest that STAT3 activation in microglia plays an important role in hyperglycemia-induced neuronal apoptosis in the diabetic hippocampus and provide a potential therapeutic benefit of STAT3 inhibition in microglia for preventing diabetic neuronal lesions.