The mechanistic role of microglial activation in Alzheimer's disease pathology is typically investigated using mouse models with aggressive amyloid accumulation, leaving the dynamics of microglial responses under the relatively slow deposition of amyloid-β (Aβ) characteristic of the early stages of the disease poorly understood. In this study, we examined microglial gene expression in the brains of AppNL-F knock-in mice, which gradually develop Aβ pathology in an aging-dependent manner without amyloid-β precursor protein overexpression. Quantitative PCR (qPCR) analysis revealed that microglial gene expression presents a stepwise activation pattern: early-induced genes increased at 12 months, whereas late-induced genes emerged at 18 months. Notably, neither group showed further induction at 24 months despite continued Aβ accumulation, indicating that microglial activation does not scale proportionally with the amyloid burden. Several canonical components of the disease-associated microglia program were not induced in AppNL-F mice, whereas a set of previously unrecognized microglial genes (Ly86, Snx20, and Pram1) was upregulated. The induction of these novel genes was preserved in the brains of Trem2 R47H knock-in mice, corroborating that the R47H variant exhibits only mild, if any, phenotype. Immunoblotting of selected proteins confirmed these qPCR-based findings. Together, these results reveal a stepwise mode of microglial gene activation under slow amyloid progression and identify novel genes that may be relevant to the early stages of Alzheimer's disease.

The TREM2 R47H variant increases the risk of Alzheimer's disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the AppNL-F background and compared it with a Trem2 knockout (KO) line to assess the degree of TREM2 functional impairment. Accumulation of amyloid β 42 and formation of dystrophic neurites were increased in Trem2 KO mice but not in Trem2 R47H KI mice at 18 or 24 months. qPCR and transcriptomic analyses revealed Trem2 KO mice showed deficits in upregulation of microglial genes while Trem2 R47H KI mice showed a response similar to control mice. Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice. Among the differentially expressed genes, Pmel and Gpnmb were or tended to be downregulated in Trem2 R47H KI as well as in Trem2 KO mice indicating their involvement in AD pathogenesis. These results clearly indicate that the TREM2 R47H variant confers a mild, rather than null, effect on microglial alterations during AD development and that Trem2 R47H KI mice should be used to understand pathological mechanism elicited by TREM2. Further identification and characterization of genes differentially expressed in Trem2 R47H KI mice will provide important insights into how the TREM2 risk variant modulates Alzheimer's disease-related pathology.

Proline-rich transmembrane protein 2 (PRRT2) plays a pivotal role in the control of voluntary movements, as PRRT2 mutations cause paroxysmal kinesigenic dyskinesia (PKD) in a loss-of-function manner. Although the cerebellum is considered a region responsible for PKD, we recently reported that Prrt2 also regulates dopaminergic activity in the striatum, suggesting that Prrt2 functions not only in the cerebellum but also in the basal ganglia motor circuits. However, the relationship between neuronal cell types expressing Prrt2 and motor functions remains poorly understood. In this study, we determined the neurochemical types of Prrt2-positive neurons using immunofluorescence staining of mouse midbrain primary neurons and brain sections. Prrt2 was expressed mainly in glutamatergic and GABAergic neurons, but not in dopaminergic or cholinergic neurons. We found that Prrt2 was expressed preferentially in Vglut1-positive, rather than Vglut2-positive, cortical projection neurons and cerebellar granule cells, and in GABAergic medium spiny neurons of the basal ganglia, where Prrt2 was localized in axonal tracts and at or near presynaptic terminals. Taken together, we conclude that Prrt2 is variably expressed across excitatory and inhibitory neurons in motor-related neural circuits, where it might play more diverse roles in the regulation of neuronal excitability and voluntary movement.

Abstract Mutations of proline-rich transmembrane protein 2 (PRRT2) lead to dyskinetic and convulsive disorders such as paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizure and hemiplegic migraine. PKD is characterized by attacks of involuntary movements precipitated by suddenly initiated motion. Previous studies have shown that PKD might be caused by cerebellar dysfunction; however, considering widespread expression of Prrt2 in the whole brain, it is likely that some other motor-related regions including the basal ganglia, where dopaminergic neurons are most abundant in the brain, might also be a part of pathogenesis of PKD. Here, we generated Prrt2 knock-in (KI) mice harboring mutation c.672dupG that mimics the human pathological mutation c.649dupC and investigated the role of Prrt2 in the basal ganglia. The mutant transcript and protein were abolished within the striatum, confirming loss-of-function nature of PKD and related disorders. Importantly, intrastriatal microdialysis revealed that the Prrt2 mutation dramatically elevated extracellular dopamine levels during the depolarized state, which might result from the increase in dopamine release because pharmacological inhibition of dopamine reuptake produced a greater elevation of extracellular dopamine levels in Prrt2-KI mice than in wild-type mice. Moreover, administration of L-dopa, a precursor of dopamine, exacerbated rotarod performance of Prrt2-KI mice more severely than that of wild-type mice. Overall, these findings suggest that dopaminergic dysfunction within the basal ganglia by the PRRT2 mutation might be implicated in a part of motor symptoms of PKD and related disorders.

Mutations in proline-rich transmembrane protein 2 (PRRT2) cause paroxysmal kinesigenic dyskinesia (PKD). Recently, we reported that a Prrt2 mutation exacerbated L-dopa-induced motor deficits in mice, suggesting that the basal ganglia might contribute to PKD pathology. Here, we demonstrated that the Prrt2 mutation enhanced depolarization stimuli-induced extracellular dopamine levels in the mouse striatum, which were attenuated by repeated stimulation. L-dopa administration maintained high dopamine levels in Prrt2-KI mice even during repetitive stimuli but did not affect dopamine levels in wild-type mice. Thus, the enhanced and prolonged responsiveness of dopamine release in nigrostriatal dopaminergic neurons to sequential excitation may be partially implicated in Prrt2-related dyskinesia.

(-)-Epigallocatechin-3-gallate (EGCg), a major constituent of green tea extract, is well-known to exhibit many beneficial actions for human health by interacting with numerous proteins. In this study we identified synaptic vesicle membrane protein VAT-1 homolog (VAT1) as a novel EGCg-binding protein in human neuroglioma cell extracts using a magnetic pull -down assay and LC-tandem mass spectrometry. We prepared recombinant human VAT1 and analyzed its direct binding to EGCg and its alkylated derivatives using surface plasmon resonance. For EGCg and the derivative NUP-15, we measured an association constant of 0.02-0.85 x10(3) M(-1)s(-1) and a dissociation constant of nearly 8 x 10(-4) s(-1). The affinity K-m(affinity) of their binding to VAT1 was in the 10-20 mu M range and comparable with that of other EGCg-binding proteins reported previously. Based on the common structure of the compounds, VAT1 appeared to recognize a catechol or pyrogallol moiety around the B-, C- and G -rings of EGCg. Next, we examined whether VAT1 mediates the effects of EGCg and NUP-15 on expression of neprilysin (NEP). Treatments of mock cells with these compounds upregulated NEP, as observed previously, whereas no effect was observed in the VAT1-overexpressing cells, indicating that VAT1 prevented the effects of EGCg or NUP-15 by binding to and inactivating them in the cells overexpressing VAT1. Further investigation is required to determine the biological significance of the VAT1-EGCg interaction.

We investigated the alterations in autophagy-related molecules in neurons differentiated from induced pluripotent stem cells obtained from patients with Alzheimer's disease (AD). Consistent with our previous microarray data, ATG4A protein was upregulated in the neurons derived from a familial AD patient with an APP-E693Δ mutation who showed accumulation of intracellular amyloid β peptide (Aβ). This upregulation was reversed by inhibiting Aβ production, suggesting that the intracellular Aβ may be responsible for the upregulation of ATG4A. The LC3B-II/LC3B-I ratio, an index of autophagosome formation, was lower in the neurons derived from the AD patient with APP-E693Δ as well as the neurons derived from other familial and sporadic AD patients. These findings indicate that dysregulation of autophagy-related molecules may accelerate the pathogenesis of AD.

The onset of Alzheimer's disease (AD) is characterized by accumulation of amyloid β peptide (Aβ) in the brain. Neprilysin (NEP) is one of the major Aβ-degrading enzymes. Given findings that NEP expression in the brain declines from the early stage of AD before apparent neuronal losses are observed, enhancement of NEP activity and expression may be a preventive and therapeutic strategy relevant to disease onset. We screened for compounds that could enhance the activity and expression of NEP using a polyphenol library previously constructed by our research group and investigated the structure-activity relationships of the identified polyphenols. We found that amentoflavone, apigenin, kaempferol, and chrysin enhanced the activity and expression of NEP, suggesting that chemical structures involving a double bond between positions 2 and 3 in the C ring of flavones are important for NEP enhancement, while catechol or pyrogallol structures, except for the galloyl group of catechins, abolished these effects. Moreover, natural compounds, such as quercetin, were not effective per se, but were changed to effective compounds by adding a lipophilic moiety. Using our study findings, we propose improvements for dietary habits with experimental evidence, and provide a basis for the development of novel small molecules as disease-modifying drugs for AD.

We investigated the alterations in autophagy-related molecules in neurons differentiated from induced pluripotent stem cells obtained from patients with Alzheimer's disease (AD). Consistent with our previous microarray data, ATG4A protein was upregulated in the neurons derived from a familial AD patient with an APP-E693Δ mutation who showed accumulation of intracellular amyloid β peptide (Aβ). This upregulation was reversed by inhibiting Aβ production, suggesting that the intracellular Aβ may be responsible for the upregulation of ATG4A. The LC3B-II/LC3B-I ratio, an index of autophagosome formation, was lower in the neurons derived from the AD patient with APP-E693Δ as well as the neurons derived from other familial and sporadic AD patients. These findings indicate that dysregulation of autophagy-related molecules may accelerate the pathogenesis of AD.

Mutations of proline-rich transmembrane protein 2 (PRRT2) lead to dyskinetic disorders such as paroxysmal kinesigenic dyskinesia (PKD), which is characterized by attacks of involuntary movements precipitated by suddenly initiated motion, and some convulsive disorders. Although previous studies have shown that PKD might be caused by cerebellar dysfunction, PRRT2 has not been sufficiently analyzed in some motor-related regions, including the basal ganglia, where dopaminergic neurons are most abundant in the brain. Here, we generated several types of Prrt2 knock-in (KI) mice harboring mutations, such as c.672dupG, that mimics the human pathological mutation c.649dupC and investigated the contribution of Prrt2 to dopaminergic regulation. Regardless of differences in the frameshift sites, all truncating mutations abolished Prrt2 expression within the striatum and cerebral cortex, consistent with previous reports of similar Prrt2 mutant rodents, confirming the loss-of-function nature of these mutations. Importantly, administration of l-dopa, a precursor of dopamine, exacerbated rotarod performance, especially in Prrt2-KI mice. These findings suggest that dopaminergic dysfunction in the brain by the PRRT2 mutation might be implicated in a part of motor symptoms of PKD and related disorders.

Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer's disease, as well as other neurodegenerative disorders. TREM2 is glycosylated in vitro and in vivo, but the significance of the modification is unknown. We previously established a sensitive and specific reporter cell model involving cultured Jurkat cells stably expressing a luciferase reporter gene and a gene encoding a TREM2DAP12 fusion protein to monitor TREM2-dependent signalling. In the present study, we prepared modified reporter cells to investigate the role of the N-glycans at N20 and N79. We show that the N-glycans at N79 have a requisite role in translocation of TREM2 to the cell surface, while the N-glycans at both N20 and N79 have a critical role in intracellular signal transduction. Our results indicate that structural changes to the TREM2 N-glycans may cause microglial dysfunction that contributes to the pathogenesis of neurodegenerative disorders, and that maintaining the integrity of TREM2 N-glycosylation and the responsible glycosyltransferases may be a novel therapeutic strategy to treat these disorders.

This paper presents a time-to-digital converter/analog-to-digital-converter (TDC/ADC) hybrid LiDAR system-on-chip (SoC) to realize reliable self-driving systems. The smart accumulation technique (SAT) is proposed to achieve both 200-m and high-pixel-resolution range imaging, which was untrodden with conventional LiDARs. The "smart" accumulation is realized by a simple object recognition strategy with small circuit overhead. When compared to conventional accumulations, the LiDAR range is enhanced without degrading the pixel resolution. Moreover, a TDC/ADC hybrid architecture is proposed to achieve a wide-distance-range LiDAR with a small silicon area and short-range precision. To minimize the ADC cost, a residue-quantizing noise-shaping (RQNS) SAR ADC is proposed. The prototype LiDAR SoC is fabricated in the 28-nm CMOS technology and integrated into the silicon photomultiplier (SiPM)-based LiDAR system. LiDAR measured with 240 x 96 pixels at 10 frames/s achieves a measurement range of 200 m with a 70-klx direct sunlight: the measurement range is 2x longer than conventional designs. Furthermore, our LiDAR achieves 4x higher effective pixel resolution compared to conventional designs using simple accumulation. A 3-D point-cloud image acquired with a real-life environment is presented.

Long-range and high-pixel-resolution LiDAR systems, using Time-of-Flight (ToF) information of the reflected photon from the target, are essential upon launching safe and reliable self-driving programs of Level 4 and above. 200m long-range distance measurement (DM) is required to sense proceeding vehicles and obstacles as fast as possible in a highway situation. To realize safe and reliable self-driving in city areas, LiDAR systems uniting wide angle-of-view and high pixel resolution are required to fully perceive surrounding events. Moreover, these performances must be achieved under strong background light (e.g., sunlight), which is the most significant noise source for LiDAR systems. To accomplish a 100m-range DM, an accumulation of the DM results through several pixels is utilized to improve the S/N ratio with 70klux background light [1]. Here, S is the number of photons reflected from the target and N as the number of background light photons. However, if the range is extended to 200m under similar condition of the laser power and frame rate (FPS), 16x more pixel accumulation is required. Such pixel accumulation leads to blurring the range image, and hence, a serious oversight in the surrounding events, such as a flying-out pedestrian, may occur, not suiting self-driving applications. Furthermore, the Time-to-Digital Converter (tDC) based ToF measurement is activated only when 2 or more photons are detected simultaneously [1], and thus, is not suitable for the 200m long-range DM where few photons are reflected from the target. On the other hand, ToF measurements using ADCs, which can continuously quantize the silicon photomultiplier (SiPM) output and can sense single-photon events, suits long-range measuring purposes well [2]. However, a number of accumulations should still be required to accomplish 200m-range DM, and hence, low resolution is inevitable. In addition, the SoC cost is critical. To enhance the short-range DM resolution by using ADCs, the required sampling rate is over 10GS/s; upon realizing a 20ch AFE, such an ADC array alone may occupy an area of over 10mm2 and consume huge power [3].

Chemical recycling of carbon fiber reinforced plastic (CFRP) containing an amine-cured epoxy as the matrix resin was investigated with a process using supercritical alcohols or ketones as solvents. Amine cured epoxy resin was decomposed by a supercritical solvent (methanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, acetone, or methyl ethyl ketone) at 320 degrees C in the reaction time range 6-120 min. The decomposition rate depended on the solvent, and super- and subcritical acetone were ultimately selected as optimal for rapidly degrading the matrix resin. The decomposition rate of the epoxy resin using supercritical acetone was expressed by a surface reaction and shrinking core model. The recovered carbon fibers from the CFRP retained the shape of the plain fabric sheets and their tensile strength reduction was negligible. (C) 2016 Elsevier B.V. All rights reserved.

Radiation induced point defect-light element impurity complexes, basically CiOi, are used widely for lifetime control in power devices for hybrid cars. Recently, not only CZ, but also FZ and epitaxial wafers have been examined as candidates. It has been suggested by luminescence study that CiOi behaved differently during annealing in crystals from different origins. The behavior of CiOi (and VO) during annealing was examined by highly sensitive infrared absorption spectroscopy (IR). CiOi concentration ([CiOi]) after irradiation depended strongly on the growth techniques and as-grown carbon ([C]) and oxygen ([O]) concentrations. In the basic C-rich MCZ case, CiOi and VO reacted with each other and decreased steadily with annealing temperature increase. They mostly disappeared at 400 degrees C. In low [C] CZ case, CiOi residual ratio (RR = alpha 400 degrees C/alpha(RT), a is the absorption coefficient) was higher, probably due to low reaction probability of much lower [CiOi] with VO. In FZ silicon, CiOi residual ratio was low, probably due to rapid break. Thus, IR made systematic and quantitative analysis compared to the luminescence study. In nitrogen-doped FZ silicon, NV was observed in as-grown crystals. N-2 was modified by irradiation and complicated reaction took place with V or I by annealing. This would affect the CiOi behavior. (C) 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

BACKGROUND:The authors have previously reported development of a novel immunochromatographic device (DK13-PG-001) for specific detection of Porphyromonas gingivalis (Pg). In this study, clinical usefulness of the detection device during periodontal therapy is presented.METHODS:The multicenter study was conducted with 62 patients contributing 118 periodontitis sites with probing depth (PD) of 4 to 9 mm. Subgingival plaque samples were used for detection of Pg by DK13-PG-001 and the PCR-invader method at: 1) baseline (BL); 2) reevaluation (RE; after scaling and root planing); and 3) final evaluation (FE; after local drug delivery system). Periodontal examinations were performed concurrently with the test for Pg detection. Plasma immunoglobulin G (IgG) titers against Pg were also determined in patients using an enzyme-linked immunosorbent assay.RESULTS:DK13-PG-001 score and number of Pg by the PCR-invader method showed a strong correlation (r = 0.862) at three stages during periodontal therapy (n = 354). High sensitivity and specificity of DK13-PG-001, in comparison with the PCR-invader method, were shown. A significant correlation was found among device score, number of Pg by the PCR-invader method, and PD and clinical attachment level at BL and RE. Plasma IgG titers against Pg were significantly reduced at FE in comparison with BL. Weak but significant correlations between IgG titers and device scores were shown at BL and FE.CONCLUSION:Results suggest the DK13-PG-001 device is a useful tool for detection of Pg in dental offices and can aid clinical evaluation of the extent of periodontitis and therapeutic efficacy.

s | 13 significant differences in the amyloid beta protein, Neprilysin (NEP), and SOX2 levels were not observed among the groups. Conclusion: Our study showed that a single dose of 1X10^6 hUCB-MSCs injected intravenously into AD transgenic mice resulted in neither delivery into the brain nor generation of therapeutic benefits via paracrine activity. In order to utilize the intravenous route as an effective delivery route for AD stem cell therapy, it will be crucial to perform additional studies on how to increase the permeability of the BBB and how to decrease the entrapment of cells in organs such as the lung and liver. PT578 Endothelial-monocyte-activating polypeptide-2 (EMAP-2) may be a novel treatment target of Alzheimer’s disease Sooah Janga,c, Jihyeon Jeonga,d, Eosu Kima,c,d, Chul Hoon Kima,b,d, Kee Namkoonga,c Department of aPsychiatry and bPharmacology, cInstitute of Behavioral Science in Medicine, dBrain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea Abstract Inflammation has been raised as a candidate of unifying pathogenesis and a target of disease modifying strategy for Alzheimer’s disease(AD). A cytokine, endothelial-monocyteactivating polypeptide-2 (EMAP-2) which amplifies actions of tumor necrosis factor alpha (TNF-alpha), might be an important target, since it is involved in microglial activation and neuronal death. We hypothesize that EMAP-2 is associated with the Alzheimer’s disease, and anti-EMAP-2 antibody could have therapeutic effects on cognitive impairment in amyloid betainduced AD model animals. We investigated the association between the EMAP-2 gene, the -9299A/G polymorphism and cognitive impairment in 641 subjects aged from 60 to 80. In addition, we compared EMAP-2 concentration in peripheral blood among people with AD (n = 30), mild cognitive impairment (n = 29), or normal cognition (n = 27). Finally, we examined the effects of anti-EMAP-2 antibody following injecting it to AD model rats on cognitive function using water maze and passive avoidance tests and on a level of cell death in the brain tissue using TUNEL assay. We found a significant association between the -9299A/G polymorphism (GG vs AG/AA) of EMAP-2 gene and cognitive impairment. GG homozygote compared to A-allele carriers was related to lower mini-mental status examination score (p = 0.001). In addition, EMAP-2 level was significantly higher in the peripheral blood of people with AD than in that of healthy control group (p = 0.05). In the AD model rats, injection of EMAP-2 antibody improved short-term memory (p < 0.01) and fear memory (p < 0.05), and lowered the levels of neuronal cell death in the brain tissue (p < 0.05) Our results suggested a possible involvement of EMAP-2 in AD pathogenesis, as well as the potential of humanized antiEMAP-2 antibody as a novel option for AD treatment.Inflammation has been raised as a candidate of unifying pathogenesis and a target of disease modifying strategy for Alzheimer’s disease(AD). A cytokine, endothelial-monocyteactivating polypeptide-2 (EMAP-2) which amplifies actions of tumor necrosis factor alpha (TNF-alpha), might be an important target, since it is involved in microglial activation and neuronal death. We hypothesize that EMAP-2 is associated with the Alzheimer’s disease, and anti-EMAP-2 antibody could have therapeutic effects on cognitive impairment in amyloid betainduced AD model animals. We investigated the association between the EMAP-2 gene, the -9299A/G polymorphism and cognitive impairment in 641 subjects aged from 60 to 80. In addition, we compared EMAP-2 concentration in peripheral blood among people with AD (n = 30), mild cognitive impairment (n = 29), or normal cognition (n = 27). Finally, we examined the effects of anti-EMAP-2 antibody following injecting it to AD model rats on cognitive function using water maze and passive avoidance tests and on a level of cell death in the brain tissue using TUNEL assay. We found a significant association between the -9299A/G polymorphism (GG vs AG/AA) of EMAP-2 gene and cognitive impairment. GG homozygote compared to A-allele carriers was related to lower mini-mental status examination score (p = 0.001). In addition, EMAP-2 level was significantly higher in the peripheral blood of people with AD than in that of healthy control group (p = 0.05). In the AD model rats, injection of EMAP-2 antibody improved short-term memory (p < 0.01) and fear memory (p < 0.05), and lowered the levels of neuronal cell death in the brain tissue (p < 0.05) Our results suggested a possible involvement of EMAP-2 in AD pathogenesis, as well as the potential of humanized antiEMAP-2 antibody as a novel option for AD treatment. PT579 Disease-modifying therapy through enhancement of neuronal Aß-degrading enzyme neprilysin activity for Alzheimer’s disease Nobuhisa Iwata, Masashi Asai, Daisuke Hatta, Mikako Honda, Yuma Hori, Momoka Kinoshita, Naotaka Kuroda, Kaname Ohyama, Keiro Shirotani, Takashi Tanaka, Kaori Watanabe Nagasaki University, Japan Abstract Aggregation and deposition of amyloid-β peptide (Aβ) in the brain are triggering events of the long-term pathological cascade of Alzheimer’s disease (AD), and are closely associated with the metabolic balance between Aβ anabolic and catabolic activities. As almost all familial AD mutations cause an increase in the anabolism of a particular form of Aβ, Aβ1–42, leading to Aβ deposition and accelerating AD pathology, a chronic reduction in the catabolic activity would also promote Aβ deposition. Neprilysin is a rate-limiting peptidase involved in brain Aβ catabolism. Mounting evidence that expression levels of neprilysin are decreased in the hippocampus and cerebral cortex of AD patients from the early stages of disease development and also with aging in humans, suggests a close association of neprilysin with the etiology and pathogenesis of AD. Thus, a subtle but long-term decline in neprilysin activity appears to be at least partly responsible for the memory-related symptoms of AD, and up-regulation of neprilysin would be a promising strategy for disease-modifying therapy of AD. We screened a compound modulating brain neprilysin activity and/or gene expression using a natural product library, and found that catechins, such as EGCg were capable of up-regulating neprilysin via gene expression. However, their bioavailabilities and blood-brain barrier permeability are not always so good, because these compounds are highly hydrophilic. So, we synthesized aliphatic catechin derivatives by introducing an alkyl chain or aliphatic moiety into EGCg to increase Log P values. Interestingly, some of the aliphatic catechin derivatives more strongly up-regulated not only neprilysin but also α-secretase, which acts to preclude Aβ production, than EGCg did. The aliphatic catechins would be promising drug candidates for therapy and prevention of AD. Currently, we are analyzing their in vivo effects on up-regulation of neprilysin. PT580 Alteration of neuronal nitric oxide synthase dimerization contributes to the development of Alzheimer’s disease Kyoung Ja Kwon1, Ryoung Eun Kim1, Seung Hwa Park1, Chan Young Shin1, Du-Hyong Cho2,* and Seol-Heui Han1,* 1Department of Neurology, Konkuk University Medical Center and Department of Neuroscience, Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul 143–701, Korea. 2Department of Pharmacology, School of Medicine, Eulji University, 77, Gyeryong-ro, 771 Beon-gil, Jung-gu, Daejeon