Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer's model mice.

Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer's disease (AD), also known as "type 3 diabetes". Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, ß-amyloid oligomers, plaques, phosphorylated tau, and GSK3ß expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.

Association of trabecular meshwork height with steroid-induced ocular hypertension.

It is important to identify at-risk patients prior to administering steroid injections to prevent avoidable irreversible blindness inducted by steroid-induced ocular hypertension (SIOH). We aimed to investigate the association of SIOH following intravitreal dexamethasone implantation (OZURDEX) using anterior segment optical coherence tomography (AS-OCT). We conducted a retrospective case control study to assess the association between trabecular meshwork and SIOH. A total of 102 eyes that underwent both AS-OCT and intravitreal dexamethasone implant injection were divided into the post-steroid ocular hypertension and normal intraocular pressure groups. Ocular parameters that can contribute to intraocular pressure were measured using AS-OCT. Univariable logistic regression analysis was used to calculate the odds ratio of the SIOH and significant variables were further analyzed using a multivariable model. Trabecular meshwork (TM) height was significantly shorter in the ocular hypertension group (716.13 ± 80.55 µm) than that in the normal intraocular pressure group (784.27 ± 82.33 µm) (p < 0.001). The receiver operating characteristic curve technique analysis showed that the optimal cut-off of ≥ 802.13 µm for TM height specificity was 96.2%, and TM height with < 646.75 µm had a sensitivity of 94.70%. The odds ratio of the association was 0.990 (p = 0.001). TM height was identified as a newly observed association with SIOH. TM height can be assessed using AS-OCT, with acceptable sensitivity and specificity. Caution must be exercised while injecting steroids in patients with short TM height (especially < 646.75 µm) as it may cause SIOH and irreversible blindness.

Predicting the safety zone for steroid-induced ocular hypertension induced by intravitreal dexamethasone implantation.

BACKGROUND/AIMS: This study aimed to predict the possibility of steroid-induced ocular hypertension (OHT) after intravitreal dexamethasone (DEX) implantation and to identify a proper safety zone for such injections. METHODS: A cross-sectional observational study was conducted and included 908 patient eyes that underwent DEX implant injection due to various retinal diseases. Intraocular pressure (IOP) was measured before injection, at 1 week, and at 1, 2, 3, 6 and 12 months thereafter. Eyes of enrolled patients were divided into the OHT and normal IOP groups. Univariable logistic regression analysis was used to assess significant associations between steroid-induced OHT and covariates; significant and previously reported significant variables were analysed with a multivariable model, and predictive nomograms were developed. RESULTS: Age, sex, axial length, glaucomatous eye, neovascular glaucoma, secondary glaucoma, uveitis history, hypertension, depression, diabetes mellitus and a history of previous laser-assisted in-situ keratomileusis or laser-assisted subepithelial keratectomy were significantly related to steroid-induced OHT (p<0.05). The calibration plot revealed good prediction under a predicted value of 0.4. Cut-off values for 80%, 86%, 91%, 95% and 98% sensitivity and specificity were offered for the safety zone after intravitreal DEX implantation. CONCLUSION: We developed two nomograms to predict a safety zone for intravitreal DEX implantation. These can be used to identify individuals who may be safely prescribed steroid treatments and for whom extra caution should be exercised.

Effects of Glaucoma Medication on Dry Eye Syndrome and Quality of Life in Patients with Glaucoma.

PURPOSE: To investigate ocular surface diseases and changes in the quality of life of patients using glaucoma medications. METHODS: Participants were divided into the normal (31 individuals, 62 eyes) and glaucoma medication (30 patients, 60 eyes) groups. Changes in tear break-up time, lipid layer thickness (LLT), corneal and conjunctival staining scores, ocular surface disease index (OSDI), and Visual Function Questionnaire 25 (VFQ-25) score were assessed for 1 year. RESULTS: The change in mean LLT was lower in glaucomatous eyes than in control eyes (p = 0.019) after 1 year. The results of OSDI deteriorated (p' = 0.008), but conjunctival staining and Schirmer test results showed improvement in glaucomatous eyes compared to those in control eyes (p' =0.035 and 0.009, respectively). The average LLT decreased at 6 and 12 months, but there was no change at 24 months. In pairwise analysis, the decrease in LLT over the first 6 months was statistically significant (p < 0.001) and remained unchanged until 24 months. Among the VFQ items, scores for near activity and social function deteriorated over 1 year in the medication group (p' = 0.033 and 0.015, respectively). However, there was no difference in the total VFQ score. CONCLUSIONS: Significant reduction in LLT and deterioration of OSDI were observed in the medication group compared to the control group. However, this deterioration was observed only in the first 6 months. There was no significant difference in the VFQ total score. Nonetheless, there were significant differences in near activity and social function between the control and medication groups. Therefore, the results of this study showed that although glaucoma medication worsened eye dryness, the change was limited and did not worsen the quality of life. Glaucoma medication should be used with the consideration that they can limit near activity and social functioning.

Investigating the Relationship between Glaucoma Prevalence and Trabecular Meshwork Length.

Glaucoma is one of the most common causes of blindness worldwide, but the risk factors of glaucoma are yet to be fully understood. We investigated the relationship between the prevalence of glaucoma and trabecular meshwork (TM) length by comparing the mean TM length of a South Korean population with that of another ethnic population. We included 250 eyes of 125 patients who underwent anterior segment optical coherence tomography at Yonsei University Gangnam Severance Hospital between January 2015 and December 2017. We measured the distance from the scleral spur to Schwalbe's line in patients with open and closed angles and calculated the TM length using the open- and closed-angle ratios in the general population. The mean TM length of the patients in our study was 752 ± 116 µm. Considering the compensated data, the estimated true mean TM length in the Korean population was 793 ± 76 µm, which was similar to the mean TM length of a previously evaluated Hispanic population, but differed significantly from those of previously evaluated Asian (Chinese), Caucasian, and African-American populations (p < 0.05). Our results support the hypothesis that the development of glaucoma would be affected by TM length.

Progression patterns of normal-tension glaucoma groups classified by hierarchical cluster analysis.

OBJECTIVES: To investigate differences in progression patterns of normal-tension glaucoma (NTG) patients in three clusters classified by hierarchical cluster analysis (HCA). MATERIALS AND METHODS: In a retrospective study, 200 eyes of NTG patients classified by HCA in 2015 who were followed up to the current date were evaluated. Peripapillary retinal nerve fibre layer (RNFL) thicknesses were measured by Cirrus HD-OCT and progression rate was calculated by trend analysis (Guided Progression Analysis [GPA]). VF progression rate was evaluated by linear regression analysis of mean deviation (MD). Progression patterns of three clusters were compared by histograms. RESULTS: In total, 153 eyes of 153 patients were followed up. Mean observation period was 5 years. RNFL reduction rate was -0.83 µm/year in cluster 1, which showed early glaucomatous damage in previous reports; -0.45 µm/year in cluster 2, which showed moderate glaucomatous damage; and -0.36 µm/year in cluster 3, which showed young and myopic glaucomatous damage. The progression pattern of cluster 3 showed a double-peak distribution; RNFL reduction rate was 0.11 µm/year in the non-progressive group and -1.07 µm/year in the progressive group. CONCLUSION: The progression patterns were different among three NTG groups that were divided by HCA. In particular, the group of young and myopic eyes showed a mixture of two different patterns.

Effect of systemic blood pressure on optical coherence tomography angiography in glaucoma patients.

BACKGROUND: The association between retinal microvascular structure and glaucoma has been revealed in multiple studies using optical tomography angiography (OCTA), but limited information on the macular vessel density (mVD) in patients with glaucoma is available. In this study, we tried to identity the factors that affected macular VD (mVD) in glaucomatous eyes. METHODS: This retrospective cross-sectional study evaluated OCT and OCTA images from 92 eyes from 58 healthy subjects and 179 eyes from 103 glaucoma patients using the SD-OCT database from July 2017 to July 2018. Glaucomatous eyes were further divided into two groups according to history of disc haemorrhage (DH). Association between mVD and demographic characteristics, ganglion cell-inner plexiform layer (GCIPL) thickness, visual field mean deviation (MD) and systemic blood pressure was analysed in each group. RESULTS: In both healthy and glaucomatous eyes, mVD was inversely associated with age (ß = -0.035, P = 0.025; ß = -0.039, P = 0.018). In the glaucomatous eyes, mVD was significantly decreased, as the MD value was worse (ß = 0.109, P = 0.002). In glaucomatous eyes with DH, mVD decreased as blood pressure increased (ß = -0.111, P = 0.003) CONCLUSIONS: Reduced mVD is more common in older individuals in both healthy and glaucomatous eyes, and correlates with functional deterioration than structural damage in glaucomatous eyes. In glaucomatous eyes with DH, high systemic BP is associated with a reduction in mVD. This may indicate that glaucoma patients with DH are more susceptible to vascular damage secondary to hypertension.

Development of a nomogram using fundus photography to predict glaucoma progression in patients showing disc hemorrhage.

To develop a nomogram to predict the progression of glaucoma by fundus photography in patients with disc hemorrhage. Retrospective review of the medical records of patients with disc hemorrhage, which was detected during follow up with open angle glaucoma, from January 2010 to March 2018. Patients were divided into glaucoma progression (n = 52) or non-progression (n = 38) groups. We assessed proximal location and morphology of disc hemorrhage; relationship to retinal nerve fiber layer defects with disc hemorrhage; and angular extent of disc hemorrhage, between groups using fundus photography. Multiple logistic regression analysis was performed to select prognostic factors, and we constructed a nomogram to predict glaucoma progression. The number of disc hemorrhage at the border of retinal nerve fiber layer defects (P = 0.001) and peripapillary disc hemorrhage (P = 0.008) were significantly higher in the progression group. We used angular extent; location of disc hemorrhage with retinal nerve fiber layer defects; and proximal location of disc hemorrhage to construct the nomogram. The area under the receiver operating characteristic curve of the nomogram was 0.847. We created the nomogram using fundus photography in patients showing disc hemorrhage as a novel and accurate screening method to predict glaucoma progression and aid clinicians to decide on the best treatment plan.

Factors associated with macular vessel density measured by optical coherence tomography angiography in healthy and glaucomatous eyes.

PURPOSE: To investigate factors associated with macular vessel density and to analyze their effects according to glaucoma stage. STUDY DESIGN: Retrospective cross-sectional study. METHODS: A total of 72 healthy eyes and 147 open-angle glaucomatous eyes were studied. All eyes underwent optical coherence tomography and visual field examinations. Clinical variables were compared according to the glaucoma stage. Relationships between macular vessel density (mVD) and other variables were analyzed using linear regression and segmented analyses. RESULTS: Age (P = 0.010) and signal strength (P < 0.001) were associated with macular vessel density in healthy eyes. In glaucomatous eyes, age, signal strength, ganglion cell-inner plexiform layer (GCIPL) thickness, and mean deviation (MD) correlated with macular vessel density (all P ≤ 0.005). When analyzed by glaucoma stage, age correlated with macular vessel density in early (P = 0.017 and all P ≤ 0.012, respectively) and moderate (P = 0.002 and all P ≤ 0.001, respectively) glaucoma. Conversely, GCIPL thickness was associated with macular vessel density (P = 0.004). According to segmented analysis between MD and mVD, the MD value at the change point for mVD was -17.92 dB, which was much lower than that for GCIPL thickness (-5.83 dB). CONCLUSION: Signal strength was the most significant factor associated with macular vessel density in healthy and glaucomatous eyes. Other than signal strength, factors associated with macular vessel density of glaucomatous eyes vary according to the glaucoma stage. The segmented analysis suggests that mVD could be better than GCIPL thickness in predicting MD changes in moderate-to-advanced glaucoma.

Evaluation of the Relationship Between Age and Trabecular Meshwork Height to Predict the Risk of Glaucoma.

This study evaluated age-related trabecular meshwork (TM) height variations in the eyes of adults in different age groups. We hypothesised that a reduction in TM occurs with increasing age. This retrospective, cross-sectional, observational study was conducted at Yonsei University Gangnam Severance Hospital between January 2015 and June 2019. We randomly included 250 eyes of 125 patients who underwent anterior segment optical coherence tomography (AS-OCT). The distance from the scleral spur to Schwalbe's line in patients with normal open anterior chamber angle was measured using AS-OCT. Results were stratified based on patients' age group-≤40, 41-50, 51-60, 61-70, 71-80, and 81-92 years. Thereafter, the results were compared among the age groups. The mean TM height of the patients was 770.929 ± 76.776 µm. TM height was 853.188 ± 94.117 µm in patients aged ≤40 years; it was 815.309 ± 75.723, 798.115 ± 66.040, 770.942 ± 52.774, 726.716 ± 63.979, and 715.968 ± 63.403 µm in patients aged 41-50, 51-60, 61-70, 71-80, and 81-92 years, respectively. The TM height tended to decrease with increasing age (P < 0.001). TM height was significantly shorter in older patients than in younger ones. Therefore, TM height may change with age and may contribute to increased glaucoma risk and prevalence.

Focal lamina cribrosa defects and significant peripapillary choroidal thinning in patients with unilateral branch retinal vein occlusion.

PURPOSE: To investigate the prevalence of focal lamina cribrosa (LC) defects in patients with unilateral branch retinal vein occlusion (BRVO) and to compare ocular characteristics between eyes with and without focal LC defect and those eyes with normal-tension glaucoma (NTG). METHODS: This retrospective, cross-sectional study included 121 patients. Thirty-nine patients had unilateral BRVO (BRVO group), 36 patients had NTG (NTG group), and 36 patients had vitreous floaters, but no other ocular diseases (control group). In addition to baseline characteristics such as age, sex, refractive errors, the ocular characteristics such as peripapillary choroidal thickness (PCT), retinal nerve fiber layer thickness, and subfoveal choroidal thickness were retrospectively analyzed. RESULTS: Focal LC defects were detected in 20 eyes of 14 patients (38.9%) in the BRVO group, 24 eyes of 15 patients (41.7%) in the NTG group, and none in the control group (P<0.001). In the BRVO-affected eyes, the mean PCT was 102.7±31.1 µm in the eyes with focal LC defects, and 163.1±70.1 µm in the eyes without LC defects (P = 0.009). In the BRVO-affected eyes, the mean PCT was 102.7±31.1 µm in the eyes with focal LC defects, and 163.1±70.1 µm in the eyes without LC defects (P = 0.009). In the NTG group, the mean PCT was 133.1±48.9 µm in the eyes with focal LC defects and 170.8±81.9 µm in those without (P = 0.042). The other baseline and ocular characteristics were not significantly different between the eyes with and without focal LC defects in both the BRVO group and the NTG group. CONCLUSIONS: About 40% of the patients with unilateral BRVO had focal LC defect in the BRVO-affected eyes and unaffected fellow eyes, similar prevalence to the patients with NTG. The mean PCT was significantly thinner in the eyes with focal LC defect than those without in the patients with BRVO and those with NTG, suggesting possible pathophysiologic correlation between these two diseases.

Age as a risk factor for steroid-induced ocular hypertension in the non-paediatric population.

BACKGROUND/AIMS: To evaluate the age-related risk of steroid-induced ocular hypertension by analysing intraocular pressure (IOP) changes after intravitreal dexamethasone (DEX, Ozurdex) implant injection. METHODS: A retrospective observational study was conducted among patients (n=455; 570 eyes) who had received DEX injection. IOP was measured prior to injection and after 1 week and 1, 2, 3, 6 and 12 months. Results were divided into seven categories based on patient age: 16-30, 31-40, 41-50, 51-60, 61-70, 71-80 and 81-90 years. The IOP elevation rate was compared among the groups. RESULTS: The IOP elevation rate was 42.9% in patients aged ≤30 years (35.3%, 28.3%, 14.9%, 12.2%, 8.4% and 9.1% in the 31-40, 41-50, 51-60, 61-70, 71-80 and 81-90 groups, respectively). Regardless of how IOP was measured, there was an increasing trend in the incidence of IOP elevation with decreasing age. Furthermore, there was a significant stepwise increase in the OR with decreasing age groups. After the 51-60 group was set as the reference point, the ORs (95% CIs) were 5.048 (1.436 to 17.747), 3.671 (1.101 to 12.238), 2.538 (1.043 to 6.178), 0.947 (0.431 to 2.078), 0.713 (0.312 to 1.626) and 0.646 (0.137 to 3.048) in the ≤30, 31-40, 41-50, 61-70, 71-80 and 81-90 groups, respectively. CONCLUSION: The rate of adverse elevations in IOP after steroid use was significantly lower in older patients than in younger patients. Therefore, caution is required when prescribing steroids to younger patients (<51 years).

Significance of dynamic contour tonometry in evaluation of progression of glaucoma in patients with a history of laser refractive surgery.

AIMS: In this study, we tested the hypothesis that intraocular pressure (IOP) parameters measured by dynamic contour tonometry (DCT) would be more relevant in progression of glaucoma when there is a history of laser refractive surgery (LRS) than the IOP parameters measured by Goldmann applanation tonometry (GAT) or calculated by correction formulae. METHODS: Ninety-eight eyes in 54 patients with open-angle glaucoma and a history of LRS were included in this retrospective study. IOP was measured by both GAT and DCT during follow-up. Baseline, mean, and peak IOP, IOP fluctuation, and IOP reduction were measured by each tonometry method. Corrected IOP parameters using central corneal thickness and mean keratometry values were also analysed. Clustered logistic regression was used to identify variables correlated with progression of glaucoma. Areas under the curve (AUCs) for correlated variables were also compared. RESULTS: The mean DCT value (OR 1.36, p=0.024), peak DCT value (OR 1.19, p=0.02) and pattern SD (OR 1.10, p=0.016) were significant risk factors for progression. There was a significant difference in the predictive ability of the mean DCT and GAT values (AUC 0.63 and 0.514, respectively; p=0.01) and of the peak DCT and GAT values (0.646 and 0.503, respectively, p=0.009). The AUCs for corrected IOP did not exceed those of DCT. CONCLUSIONS: IOP measurements were more associated with progression of glaucoma when measurements were obtained by DCT than by GAT or correction formulae in eyes with a history of LRS.

Particulate matter increases beta-amyloid and activated glial cells in hippocampal tissues of transgenic Alzheimer's mouse: Involvement of PARP-1.

Exposure to air pollutants, such as particulate matter (PM), has been implicated in neurodegenerative disorders including Alzheimer's disease (AD). However, direct effects of PM on production of ß-amyloid (Aß), a key pathogenic molecule in AD, and its underlying mechanism are still elusive. Given PM's potential to induce oxidative stress in other tissues, we hypothesized that poly(ADP-ribose) polymerase (PARP-1) might be involved in PM-induced neurotoxicity. To address this, we used an ex vivo model of AD, the organotypic hippocampal slice tissue culture from old (12-14 months-of-age) triple transgenic 3xTg-AD mice. First, we observed that fine PM (aerodynamic diameter < 4 µm) can dose-dependently activate PARP-1 and decrease NAD+ levels in Neuro2A cells. PARP-1 activation did occur under concentrations of PM which did not affect cell viability. Next, we observed that direct treatment of PM increased Aß levels and activated glial cells in the ex vivo hippocampal tissues of 3xTg-AD mice. PM-induced glial activation was most prominent in CA1 region of the hippocampal tissue. Notably, we found that pharmacological inhibition of PARP-1 reversed both PM-induced Aß increase and glial activation, arguing the possible involvement of PARP-1 in PM-induced AD pathogenesis. Our findings suggest that PARP-1 might be a potential molecular target, responsible for mediating negative effects of PM on the brain. Modulating PARP-1 activity could be a promising approach to prevent or alleviate PM-related environmental neurotoxicity which could initiate AD pathogenesis.

Long-Term Culture of Organotypic Hippocampal Slice from Old 3xTg-AD Mouse: An ex vivo Model of Alzheimer's Disease.

OBJECTIVE: Conventional methods for organotypic hippocampal tissue slice culture (OHSC) have shown several disadvantages or limitations regarding age of animals used, duration of culture and difficulty using neurodegenerative models. Therefore, we tried to establish OHSC from old 3xTg-Alzheimer's disease (AD) mice for longer period (over 4 weeks) and to validate utility of this system as a valid platform for translational neuroscience of AD. METHODS: OHSC was performed with old 3xTg-AD mice (12-14 months), old wild type mice (12-14 months) and young 3xTg-AD mice (2-4 months) using serum-free medium for 4 weeks. Hippocampal structure was evaluated by 4', 6-diamidino-2-phenylindole (DAPI) intensity and neuronal metabolism was measured by Alamarblue assay. Pathologic characteristics of AD were also investigated; ß-amyloid levels by ELISA, amyloid plaque deposition by Thioflavin-S staining, and glial activation by immunohistochemistry. RESULTS: Following 4-week culture in serum-free media, hippocampal cells and layers were well preserved in cultured slices from old AD mice as was in those from young AD and old wild type mice. On the contrary, excessive regression of total visible cells was observed in conventional serum-containing medium regardless of genotype of mice. In parallel with this well preserved structure, major pathologic characteristics of AD were also well manifested in hippocampal slices from old AD mice. CONCLUSION: Our findings suggest that long-term OHSC from old 3xTg-AD mouse can serve as a promising ex vivo system for studies on pathophysiology of AD, especially with the minimum number of sacrifice of experimental animals.

Optimizing reproducibility of operant testing through reinforcer standardization: identification of key nutritional constituents determining reward strength in touchscreens.

Reliable and reproducible assessment of animal learning and behavior is a central aim of basic and translational neuroscience research. Recent developments in automated operant chamber technology have led to the possibility of universal standard protocols, in addition to increased translational potential, reliability and accuracy. However, the impact of regional and national differences in the supplies of available reinforcers in this system on behavioural performance and inter-laboratory variability is an unknown and at present uncontrolled variable. Therefore, we aimed to identify which constituent(s) of the reward determines reinforcer strength to enable improved standardization of this parameter across laboratories. Male C57BL/6 mice were examined in the touchscreen-based fixed ratio (FR) and progressive ratio (PR) schedules, reinforced with different kinds of milk-based reinforcers to directly compare the incentive values of plain milk (PM, high-calorie: high-fat/low-sugar), strawberry-flavored milk (SM, high-calorie: low-fat/high-sugar), and semi-skimmed low-fat milk (LM, low-calorie: low-fat/low-sugar) on the basis of differences in caloric content, sugar/fat content, and flavor. Use of a higher caloric content reward was effective in increasing operant training acquisition rate. Total trial number completed in FR and breakpoint in PR were higher using the two isocaloric milk products (PM and SM) than the lower caloric LM, with comparable outcomes between PM and SM conditions, suggesting that total caloric content determines reward strength. Analysis of within-session changes in response rate revealed that overall outputs in FR and PR primarily depend on the response rate at the initial phase of a session, which itself was dependent on reinforcer caloric content. Interestingly, the rate of satiation, indicated by decay in response rate within a FR session, was highest when reinforced with SM, suggesting a rapid satiating effect of sugar. The key contribution of reward caloric content to operant performance was confirmed in a multi-laboratory study using the touchscreen 5-choice serial reaction time task (5-CSRTT) reinforced by two isocaloric milk-based liquid rewards with different countries of origin, which yielded consistent performance parameters across sites. Our results indicate that milk-based liquid reinforcer standardization can be facilitated by matching caloric content across laboratories despite regional or national differences in other non-caloric aspects of the reinforcers.

Suppression of AIMP1 protects cognition in Alzheimer's disease model mice 3xTg-AD.

Neuroinflammation has been raised as a candidate of unifying pathogenesis and a target of a disease-modifying strategy for Alzheimer's disease (AD). Aminoacyl-tRNA synthetase complex (ARS)-interacting multifunctional protein 1 (AIMP1) is a cytokine that is known to amplify the actions of tumor necrosis factor-α and to be involved in microglial activation and neuronal death. In this respect, AIMP1 could be a plausible target for the treatment of AD. Therefore, we aimed to examine whether anti-AIMP1 antibody could exert therapeutic effects against cognitive impairment using 3xTg-AD mice. Through the passive avoidance test, we found that an intraperitoneal injection of anti-AIMP1 antibody over 4 weeks was effective in protecting memory function in 3xTg-AD mice (16 weeks old). In addition, to address the translational implications of AIMP1, we measured blood AIMP1 levels in patients with AD (n=22), mild cognitive impairment (n=25), and normal cognition (n=23). Blood AIMP1 levels were associated negatively with global cognitive function and were significantly higher in individuals with a higher degree of medial temporal lobe atrophy, which is one of the representative clinical markers of AD. Our results suggested a possible association of AIMP1 with AD pathogenesis, as well as the potential of the anti-AIMP1 antibody as a novel therapeutic option for AD.

Blunted response of hippocampal AMPK associated with reduced neurogenesis in older versus younger mice.

The rate of hippocampal neurogenesis declines with aging. This is partly explained by decreased neural responsiveness to various cues stimulating metabolism. AMP-activated protein kinase (AMPK), a pivotal enzyme regulating energy homeostasis in response to metabolic demands, showed the diminished sensitivity in peripheral tissues during aging. AMPK is also known to be involved in neurogenesis. We aimed to see whether AMPK reactivity is also blunted in the aged hippocampus, and thus is associated with aging-related change in neurogenesis. Following subchronic (7days) intraperitoneal and acute intracerebroventricular (i.c.v.) administration of either 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR; AMPK activator) or saline (sham) to young (16-week-old) and old (72-week-old) mice, we measured changes in AMPK activity, brain-derived neurotrophic factor (BDNF) expression or neurogenesis in the hippocampus. AICAR-induced changes in AMPK activity were observed in the hippocampus of young mice after acute i.c.v. injection. However, neither subchronic nor acute treatment induced significant changes in AMPK activity in old mice. Intriguingly, directions of AICAR-induced changes in AMPK activity were opposite between the hippocampus (decrease) and skeletal muscle (increase). ATP levels were inversely correlated with hippocampal AMPK activity, suggesting that the higher energy levels achieved by AICAR treatment might deactivate neuronal AMPK in young mice. The blunted response of AMPK to AICAR in old age was also indicated by the observations that the levels of neurogenesis and BDNF expression were significantly changed only in young mice upon AICAR treatment. Our findings suggest that the blunted response of neuronal AMPK in old age might be responsible for aging-associated decline in neurogenesis. Therefore, in addition to activation of AMPK, recovering its sensitivity may be necessary to enhance hippocampal neurogenesis in old age.