Poster Sessions

Poster Sessions 神経ネットワーク、神経画像、その他

2P-50 Folate deficiency-induced depression-like behavior, DNA hypomethylation and abnormal neuronal maturation in mice. Shoji Nishida¹，Yuko Takanaka¹，Ikuyo Harada¹，Ryo Takemura¹，Sota Asari¹，Shin Tachibana¹，Misato Tsuboi²，Yoshitaka Nakamura²，Ryota Araki¹，Takeshi Yabe¹ ¹Lab. Funct. Biomol. Chem. Pharmacol., Fac. Phramaceut. Sci., Setsunan Univ.，²Food Sci. Res. Lab. R & D Div. Meiji Co., Ltd. Since folate serves to transfer one-carbon units in various biosynthesis reactions such as methylation, folate is an essential nutrition in the development and maintenance of biological function. Previous epidemiological and clinical studies have implied that folate deficiency is one of risk factors for depression, suggesting the impact of folate on the development and maintenance in psychological function. In the present study, we investigated the effects of folate-deficiency on behavioral and neurobiological aspects by in vivo and in vitro analyses. Folate deficiency diet for 6 weeks decreased remarkably the serum folate levels in mice. The folate deficiency mice showed increased immobility in the forced swim test. In contrast, there are no differences between the control and folate deficiency mice in spontaneous locomotor activity, social behavior, motor coordination, spatial learning or anxiety-like behavior. DNA methylation levels were decreased in the hippocampus of the folate deficiency mice. In the dentate gyrus, the number of newborn cells and of doublecortin (an immature neuron marker) immunoreactive cells was increased and the number of NeuN (a neuron marker) immunoreactive newborn cells was decreased in the folate deficiency mice. In vitro studies also showed that increased immature neurons and decreased mature neurons from differentiating neural stem cells derived from mouse fetal brain were observed under the folate deficiency medium condition. Moreover, these depression-like behavior and abnormal neuronal maturation were reversed by replacement of S-adenosyl methionine, a methyl donor. These results suggest that folate deficiency-induced abnormal neuronal maturation via reduction of DNA methylation levels may be implicated in depression symptoms.		2P-51 Metabolic factors affect cognitive functions and measures of blood oxygen level dependent signals in healthy elderly. Masago Kasagi¹，Tomokazu Motegi¹，Yusuke Suzuki¹，Koichi Ujita²，Hirotaka Shimada²，Kosuke Narita¹，Masato Fukuda¹ ¹Department of Psychiatry and Neuroscience, Gunma University Graduate School of Medicine，²Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine Metabolic factors, such as insulin resistance, have been associated with some disorders in the central nervous system. Studies of elderly persons showed that there are obvious relationships between cognitive impairments and vascular dysfunction caused by increased insulin resistance. γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the human brain and plays an important role in the development of a insulin resistance. However, there are few reports on these factors as a cause of cognitive impairments. Assessment of GABA activity in the human brain in vivo has many difficulties, but 123I-iomazenil single photon emission computed tomography (SPECT) provides the binding potential of the GABA-A receptor. Moreover, brain function can be closely investigated by resting-state functional magnetic resonance imaging (MRI), which measures the magnitude of blood oxygen level dependent (BOLD) signals. In this study, as a preliminary investigation of cognitive impairments, we recruited 37 healthy elderly people (male and female) and conducted a cognitive assessment test, blood tests (metabolic and inflammatory factors), 123I-Iomazenil SPECT, and resting-state functional MRI. The subjects were divided into two groups according to their score in cognitive assessment test. In these two groups, we investigated the relationships between metabolic factors and magnitude of BOLD signals in functional MRI. A progress report on some relationships is presented. All the subjects provided their written informed consent in accordance with the Declaration of Helsinki. The Ethics Committee of Gunma University approved the study protocol. We respected the privacy of the subjects, and made sufficient effort to maintain their anonymity.

2P-52 Differentiated antidepressant-like profile of ketamine enantiomers in mouse models of depression Momoko Higuchi¹，Yukio Ago¹，Wataru Tanabe¹，Kaoru Seiriki^1,2，Hisato Igarashi¹，Atsushi Kasai¹，Kenji Hashimoto³，Hitoshi Hashimoto^1,4,5 ¹Lab. Mol. Neuropharmacol., Grad. Sch. Pharmaceut. Sci., Osaka Univ，²Inst. Acad. Initiat., Osaka Univ，³Div. Clin. Neurosci., Chiba Univ. Ctr. Forensic Mental Hlth，⁴United Grad. Sch. Child Dev., Osaka Univ，⁵Inst. Datability Sci., Osaka Univ Accumulating evidence shows that the NMDA receptor antagonist ketamine has rapid and potent antidepressant effects in major depressive disorder including treatment-resistant depression. Ketamine contains a chiral center producing two optical isomers (enantiomers), R- and S-ketamine, but comparative studies on the individual effects of its enantiomers are limited. In the present study, we examined the antidepressant-like effects of R- and S-ketamine in mouse models of depression. Either chronic corticosterone (CORT) treatment or post-weaning social isolation in male C57BL6/J mice increased immobility time in the forced swim test and decreased female preference in the female encounter test, suggesting despair-related and anhedonic-like behaviors, respectively. R-ketamine at doses of 10 and 20 mg/kg reduced immobility time of isolation-reared, CORT-treated, and vehicle-treated control mice at 30 min after the injection, while S-ketamine only at a dose of 20 mg/kg reduced immobility time of these mice. R- and S-ketamine (at least 20 mg/kg dose) also ameliorated the impaired preference for female encounter in isolation-reared and CORT-treated mice. In addition to the acute effects, R-ketamine showed sustained antidepressant effects in both isolation-reared and CORT-treated mice. The sustained antidepressant effects of S-ketamine were only observed in isolation-reared mice. These results confirm previous findings suggesting that R-ketamine exerts more potent acute antidepressant effects than S-ketamine. The sustained antidepressant effects of R- and S-ketamine differed between isolation-reared and CORT-treated models. Further analysis on these models might contribute to clarify the common and distinct neural mechanisms for antidepressant effects of ketamine enantiomers.		2P-53 Role of LOTUS, a neural circuit formation factor in memory function Ryohei Nishida，Yui Norisue，Arisa Kawashima，Tomoko Hirokawa，Yuji Kurihara，Kohtaro Takei Molecular Medical Bioscience Laboratory, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan Overcoming the higher brain dysfunction that exhibits memory disorders such as dementia is an important issue for mankind. Many psychiatric disorders caused by Nogo receptor-1 (NgR1) dysfunction have been recently reported. For example, it has been considered that schizophrenia-like disorder due to 22q.11.2 gene deficiency, one of the most noteworthy psychiatric disorders is mainly caused by loss of NgR1 gene locus. Nogo-deficient mice exhibit autism-like symptoms, whereas mice lacking Nogo display improved working memory. Thus, an association between Nogo-NgR1 mediated signaling and psychiatric disorders/memory impairment has been demonstrated. We previously identified lateral olfactory tract usher substance (LOTUS) serving as an endogenous NgR1 antagonist. Although LOTUS is abundantly expressed in the adult brain, it was reported that decrease of LOTUS expression level in hippocampus of aged rats was well associated with aging-induced impairment of memory function. Immunohistochemistry revealed that LOTUS was highly expressed in Papez neural circuits involved in memory control, suggesting a functional relationship of LOTUS with memory and learning. However, the role of LOTUS in memory function has not been determined. In this study, we examined memory function in LOTUS gene knocking out (LOTUS-KO) mice using social recognition test. We found that LOTUS-KO mice impaired social recognition when compared with wild type mice. We also found that decrease of neurogenesis in the adult hippocampus of LOTUS-KO mice. These finding suggest that LOTUS may involve in memory formation with neurogenesis.

2P-54 Aggression to intruders in nurturing male mice. Anna Andreevna Shabalova^1,2，Zhong Jin²，Liang Mingkum²，Chiharu Tsuji²，Shigeru Yokoyama²，Haruhiro Higashida² ¹United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui，²Center of Child Mental Development. Kanazawa University The development of healthy offspring needs both maternal and paternal cares. Lactating dams display aggression to protect their pups as a part of parental behavior. However, less information on requirement, hormones and mechanisms is available for sire’s aggression in protecting their biological pups. We analyzed paternal aggressive behavior in different conditions based on the Resident-Intruder Test. Latency for the resident to attack, number of attacks and duration aggression are used as the measures of aggression. After pairmates, the sires were isolated to the new individual cage for 1 week. The sires were divided to two groups according to different responses of cues. In the first group, sires were housed alone. In the second group, the sires were exposed to their dams daily for 6 hours. Following that, sires were tested for the offensive aggression using the Resident-Intruder Test for 3 consecutive days. In two groups on day 2 and day 3, sires demonstrated increasing of the aggression. However, the sires contacted with dams showed higher number of attacks and lower attack latency than sires who had not exposed to the dams. These data suggest that direct physical contact with dams is likely to be better for induction of aggression. Currently, the Resident-Intruder Test with pup-exposure is conducted. We expect that paternal aggression is evoked by pup cues through sensory inputs by pups and secondary by the dam’s cue. Likewise, we want to research possible effects of oxytocin on aggressive behavior under alone condition.		2P-55 Pathophysiological role of TRPM2 in a mouse model of chronic cerebral hypoperfusion Jun Miyanohara，Masashi Kakae，Kazuki Nagayasu，Hisashi Shirakawa，Shuji Kaneko Dept Mol Pharmacol. Grad Sch Pharm Sci, Kyoto Univ Chronic cerebral hypoperfusion is one of the most common causes of cognitive disorder, and has been shown to be associated with white matter inflammation and an increase in oxidative stress. TRPM2 is a Ca²⁺-permeable, oxidative stress-sensitive cation channel and expressed in the brain and immune cells, implying that TRPM2 could be involved in the pathophysiology of chronic cerebral hypoperfusion. Here, we compared the susceptibility to chronic cerebral hypoperfusion between wild-type (WT) and TRPM2-knockout (KO) mice using bilateral common carotid artery stenosis (BCAS) with 0.18 mm-diameter microcoils. In TRPM2-KO mice, as compared with WT, cognitive impairment and white matter injury were attenuated at 28 days after BCAS. In parallel, accumulation of microglia/macrophages was significantly reduced in the corpus callosum of KO mice. In addition, minocycline, an inhibitor of microglia, reduced accumulation of microglia/macrophages and cognitive impairment. Moreover, analysis of chimeric mice revealed that regardless of bone-marrow genotypes, TRPM2-KO improved cognitive impairment and white matter injury. These results indicate that TRPM2 contributes to the white matter injury by activation of microglia in chronic cerebral hypoperfusion.

2P-56 In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains. Ambika Krishnankutty¹，Taeko Kimura¹，Taro Saito¹，Kyota Aoyagi²，Akiko Asada¹，Shin-Ichiro Takahashi³，Kanae Ando¹，Mica Imaizumi²，Koichi Ishiguro⁴，Shin-ichi Hisanaga¹ ¹Department of Biological Sciences, Tokyo Metropolitan University，²Department of Biochemistry, Kyorin University School of Medicine，³Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo，⁴Department of Neurology, Graduate School of Medicine, Juntendo University Glycogen synthase kinase 3β (GSK3β) is a multifunctional protein kinase involved in many cellular activities including development, differentiation and diseases. GSK3β is thought to be constitutively activated by autophosphorylation at Tyr216 and inactivated by phosphorylation at Ser9. The GSK3β activity has previously been evaluated by inhibitory Ser9 phosphorylation, but it does not necessarily indicate the kinase activity itself. Here, we applied the Phos-tag SDS-PAGE technique to the analysisof GSK3β phosphoisotypes in cells and brains. There were three phosphoisotypes of GSK3β; double phosphorylation at Ser9 and Tyr216, single phosphorylation at Tyr216 and the nonphosphorylated isotype. Active GSK3β with phosphorylation at Tyr216 represented half or more of the total GSK3β  in cultured cells. Although levels of phospho-Ser9 were increased by insulin treatment, Ser9 phosphorylation occurred only in a minor fraction of GSK3β. In mouse brains, GSK3β was principallyin the active form with little Ser9 phosphorylation, and the phosphoisotypes of GSK3β changed depending on the regions of the brain, age, sex and disease conditions. These results indicate that the Phos-tag SDS-PAGE method provides a simple and appropriate measurement of active GSK3β in vivo, and the activity is regulated by the mechanism other than phosphorylation on Ser9.		2P-57 Glx level predicts the magnitude of gray matter microstructural organization in the elderlies. Tomokazu Motegi¹，Kosuke Narita¹，Kazuyuki Fujihara¹，Masato Kasagi¹，Yusuke Suzuki¹，Koichi Ujita²，Jamie Near³，Masato Fukuda¹ ¹Department of Psychiatry and Neuroscience, Gunma University Graduate School of Medicine，²Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine，³Douglas Mental Health University Institute and Department of Psychiatry, McGill University Magnetic resonance spectroscopy (MRS) enables the noninvasive characterization of brain metabolites of pathophysiological processes. Some recent MRS research revealed decreased glutamine+glutamate (Glx) level in the anterior cingulate cortex (ACC) or posterior cingulate cortex (PCC) in patients with mild cognitive impairment (MCI) and Alzheimer disease. Diffusion tensor imaging (DTI), which is also a MRI technique, can provide the magnitude of water diffusion, the degree of anisotropy, and the orientation of diffusion anisotropy. Mean diffusivity (MD) determined by DTI shows directionally average magnitude of water diffusion, which is related to the integrity of the brain tissue. Previous studies showed increased MD in healthy elderlies and patients with MCI, Alzheimer disease compared with controls not only in the white matter, but also in the gray matter. However, the knowledge of cortical MD is still limited, e.g., there are no investigations of the associations between Glx level and MD in the gray matter. In this study, we assessed associations between Glx level and magnitude of microstructural organization in the gray matter of the medial prefrontal cortex (mPFC) and PCC during normal aging by MRS with MEGA-PRESS and DTI. Healthy elderlies without dementia (age range, 50 ― 79 years) participated in this study. Because of several technical problems, some data of MRS with MEGA-PRESS were excluded. Finally, 30 MRS data sets each for mPFC and PCC were used in this study. As a result, in both mPFC and PCC, Glx levels were significantly negatively associated with mean MD in the gray matter within the same MRS ROI. In conclusion, our findings suggest that the levels of brain metabolites are associated with magnitude of microstructural organization in the gray matter.

2P-58 Structural abnormality associated with cognitive dysfunction in eating disorder Yusuke Suzuki¹，Masato Kasagi¹，Tomokazu Motegi¹，Kazuyuki Fujihara¹，Kouichi Uzita²，Kousuke Narita¹，Masato Fukuda¹ ¹Department of Psychiatry and Neuroscience, Gunma University Graduate School，²Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School Background: Patients with eating disorders (EDs) have a unique cognitive function, that is, previous reports have described that patients with EDs show disturbance of body image as well as attentive function, as compared with healthy controls (HCs). Also, another line of evidence has shown that structural cortical abnormalities can be found in ED patients. Recent findings of voxel-based morphometry (VBM) studies of EDs have revealed that a decreased gray matter (GM) volume in the temporal and occipital lobes can be observed in patients with EDs, compared with HCs. However, there are few studies of the relationship between structural changes and cognitive function in ED patients. Aim: The purpose of this MRI study is to investigate the association between brain structural abnormalities and cognitive dysfunction in ED. Methods: On twelve ED patients and twelve age- and gender-matched HCs, we conducted cognitive function tests and MRI for VBM analysis focusing on the superior temporal gyrus (STG), in which a smaller GM has been found in ED. The rapid visual information processing (RVP) and spatial recognition memory (SRM) of The Cambridge Neuropsychological Test Automated Battery (CANTAB) were used as measurements of attention and spatial memory functions, respectively. Results: In the right STG, a significantly smaller GM volume was found in ED patients than in HCs, which is consistent with previous reports. The RVP scores of ED patients were significantly lower than those of HCs. Furthermore, RVP scores correlated positively with right STG volume in all subjects, but not in each of the ED and HC groups. Conclusions: Our findings can support well the association between GM abnormalities and cognitive dysfunctions in ED patients.		2P-59 Activation of AMP-activated protein kinase induces anti-depressant like effect in olfactory bulbectomized mice Takayo Odaira，Osamu Nakagawasai，Wataru Nemoto，Kohei Takahashi，Wakana Sakuma，Ryotaro Ono，Koichi Tan-No Dept. Pharmacol., Fac. Pharm. Sci., Tohoku Med. Pharm. Univ. Recent studies have reported that physical exercise decreases depressive behaviors, and enhances hippocampal neurogenesis by activator of AMP-activated protein kinase (AMPK). However, the mechanisms underlying the anti-depressant effects via AMPK activation have remained unexplored. Thus, we investigated effect of AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on depressive-like behavior in naive and olfactory bulbectomized (OBX) mice as an animal model of depression. Mice were injected with AICAR for 1-14 days. The depressive-like behavior (immobility time) was evaluated by forced swimming test and tail suspension test. Acute treatment with AICAR did not decrease immobility time in naive mice. However, the depressive-like behaviors in OBX mice were ameliorated by chronic (14 days) but not by acute and subacute (7 days) administration of AICAR. By using a western blot, we revealed that phosphorylations of AMPK and tyrosine hydroxylase (TH) in hippocampus of OBX mice were increased by chronic administration of AICAR. These findings reveal that AMPK activation may have anti-depressant effect, and the effect may be due to stimulate TH activity by AMPK activation. Therefore, AMPK activator may become new anti-depressant drug, and also raise the possibility that its activators such as metformin and resveratrol may represent a promising therapeutic treatment for depression.

2P-60 Pendred syndrome patient specific iPSCs derived cochlea cells form intracellular PENDRIN aggregation Tsubasa Saeki¹，Makoto Hosoya²，Masato Fujioka²，Kaoru Ogawa²，Tatsuo Matsunaga^3,4，Hideyuki Okano¹ ¹Department of Physiology, Keio University School of Medicine，²Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine，³The Laboratory of Auditory Disorders and Division of Hearing and Balance Research, National Institute of Sensory Organs, National Tokyo Medical Center，⁴Medical Genetics Center, National Tokyo Medical Center Pendred syndrome is the most frequent syndromic form of hereditary hearing loss.The disease is associated with the mutations in SLC26A4 which encodes an anion exchanger PENDRIN, yet the rodent models have not recapitulated human phenotype. Previously, we generated patient-derived human induced pluripotent stem cells (hiPSCs) to model Pendred syndrome pathology and we found that the patient derived cochlear cells displayed aggregate of mutated PENDRIN protein and exhibited stress-induced cellular degeneration. To further investigate the relationship between mutated PENDRIN and the susceptibility of cellular stress, we here examined the detailed PENDRIN localization in the patient iPSCs derived-cochlear cells by using immuno-electron microscopy. We found aggregation-like dense PENDRIN accumulation in the cytoplasm of patient derived-cells when the cells were treated with a proteasome inhibitor epoxomicin. Because intracellular the protein aggregation is one of the characteristics of neurodegenerative diseases, the result suggests that the formation of PENDRIN aggregation may be involved in degenerative phenotypes of Pendred syndrome		2P-61 A novel model: Optical stimulation causes axonal degeneration mediated by axoplasmic calcium Yang Sui^1,2，Huy Bang Nguyen ^1,2，Truc Quynh Thai^1,2，Kazuhiro Ikenaka¹，Nobuhiko Ohno¹ ¹Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences.，² Department of Anatomy and Structural Biology, University of Yamanashi Mitochondrial defect is a key regulator of axonal degeneration induced by trauma and disease, but its specific spatial and temporal dynamics in degeneration of axons remain unclear. Since energy failure and Na+/Ca2+ overload also plays central roles in the axonal degeneration. We investigated morphological changes and underlying mechanisms in the acute degeneration of sensory nerve axons observed with optogenetic stimulations, which enables spatio-temporal regulation of stimulations causing degenerative changes. Mixed dorsal root ganglion (DRG) cultures were obtained from rat embryo, and codon-optimized ChIEF (oChIEF), a channel rhodopsin variant, conjugated with red fluorescent mCherry was introduced into the DRG neurons with lentiviral vectors. Simultaneously, green Ca2+-indicator, GCaMP3 or mitochondria-targeted green fluorescent Dendra2 (mitoDendra2) was introduced with other lentiviral vectors. Dominant negative mutant of Drp1, a mitochondrial fission protein (Drp1K38A), was also introduced in some cultures. Optogenetic stimulation of oChIEF caused axonal swelling followed by axonal fragmentation in a manner dependent on duration of stimulation. GCaMP3 imaging demonstrated that axoplasmic Ca2+ increase precedes the axonal swellings, and treatments with Ca2+ channel blockers ameliorated the axonal swellings. Inhibition of mitochondrial fission by overexpression of Drp1K38A elongated stationary mitochondria, inhibited mitochondrial fragmentation upon optogenetic stimulation and decreased axonal swelling. These results suggest that optical stimulation of channel rhodopsin variants causes axonal degeneration mediated by axoplasmic Ca2+ increase in sensory axons, and mitochondrial fission mediated by Drp1 exacerbates the initiation of axonal degeneration.

2P-62 Molecular mechanisms of neuronal aggregation caused by Reelin in the developing mouse neocortex Seika Inoue，Kanehiro Hayashi，Ken-ichiro Kubo，Kazunori Nakajima Department of Anatomy, Keio University School of Medicine Reelin is secreted by Cajal-Retzius cells in the marginal zone (MZ) of the developing neocortex. Reelin has a critical role in cortical development, because the Reelin-deficient mouse shows roughly inverted layers in the neocortex. We recently reported that ectopically expressed Reelin in vivo could induce neuronal aggregation with a normal birthdate-dependent “inside-out” alignment of neurons (Kubo, et al. J. Neurosci., 2010). Within this ectopic aggregate, neurons developed their processes toward the central Reelin-rich region, resembling the neurons that have normally finished migration beneath the MZ. In addition, we recently showed that Reelin transiently promotes N-cadherin-dependent adhesion among neurons (Matsunaga et al., PNAS, 2017), further supporting that Reelin directly regulates neuronal aggregation. Although several signaling pathways have been reported in the downstream of Reelin, it has not been known how N-cadherin-dependent neuronal aggregation caused by Reelin is regulated. In the present study, we introduced a Reelin expression vector with knockdown vectors for candidate molecules into the mouse embryonic neocortex using in utero electroporation. Then, we have investigated how these molecules would affect the ectopic Reelin-induced neuronal aggregation. As a result, we observed that the pattern of neuronal aggregation was altered after knockdown of Crk, C3G, or Nckβ in the migrating neurons. In addition, these phenotypes were different from each other. These results suggest that several signal pathways might be involved in distinct manners during the neuronal aggregation caused by Reelin. We will further analyze how each signaling affect the formation of the neuronal aggregates.		2P-63 Iron treatment inhibits amyloid deposition in APP transgenic mice Xuefeng Shen，Junjun Liu，Shuyu Liu，Yu Fujita，Toshiki Obara，Arisa Takebe，Mai Shimodate，Kirari Tiba，Hiroto Komano，Kun Zou Dept of Neurosci, Sch of Pharm, Iwate Med Univ Alzheimer’s disease is characterized by the formation of extracellular amyloid plaques containing the amyloid β-protein (Aβ) within the parenchyma of the brain. Aβ42, 42 amino acids in length, is considered to be the key pathogenic factor of Alzheimer’s disease. Iron deposition is found abundantly in the amyloid plaques of Alzheimer’s disease patients; however, whether iron intake exacerbates amyloid deposition in vivo is unknown. Here we treated the Alzheimer’s disease model mice with iron ion containing water and found that amyloid deposition in the brain was significantly inhibited, which was also accompanied by the decrease of iron deposition.The iron treatment did not change the over all level of iron in the brain or in the serum. Interestingly, Aβ40 generation was significantly increased by iron treatment in amyloid precursor protein (APP) overexpressing fibroblasts, whereas Aβ42 generation did not changed, which led to a decreased Aβ42/Aβ40 ratio. Because Aβ40 inhibits amyloid formation both in vitro and in vivo, our results suggest that iron may selectively enhance Aβ40 generation and inhibit the amyloid deposition via decreasing the Aβ42/Aβ40 ratio. Thus, iron supply may be used as a novel treatment for preventing Alzheimer’s disease. We are currently studying whether iron regulates  γ-secretase activity and whether other metal ions reduce the Aβ42/Aβ40 ratio.