CONVERGENT ANALYSIS OF ENDOPHENOTYPES IN PROGRESSIVE SUPRANUCLEAR PALSY

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Poster Presentations: Wednesday, July 27, 2016

central oscillator, oscillator response to light pulse, and speed of entrainment to light and mealtime. To evaluate sleep, mice received cranial implants of a modular EEG/EMG electrode grid (Pinnacle Systems). This allowed both rapid eye movement (REM) and non-REM phases to be monitored. We were particularly interested in slow wave sleep (i.e., Phase 3 of non-REM), which is essential for clearing misfolded proteins contributing to AD pathogenesis (e.g., amyloid-beta; Ab), suggesting a bidirectional relationship between sleep and AD pathology (Xie et al., 2013; Ju et al., 2014). Results: Sleep and circadian rhythm data collection is ongoing and will be collected at 6, 9, and 12 months of age. Behavioural analysis will be followed by probing the molecular processes underlying the circadian phenotype. Conclusions: The APP/PS1 mouse model of AD may be a useful model for developing interventions to improve sleep and circadian synchrony.

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IMPACT OF PRENATAL ZINC SUPPLEMENTATION ON NEUROCHEMICAL, BIOCHEMICAL AND COGNITIVE DEFICITS PRODUCED IN INFANTS OF LPS-INFECTED FEMALE RATS

Neha Sharma, Palvi Arora, Bimla Nehru, Panjab University, Chandigarh, India. Contact e-mail: [email protected] Background: Recent research revealed an association between maternal infection i. e LPS exposure during pregnancy and increased risk for CNS disorder in offsprings. The environment insults during pregnancy affects rat brain development and exerts alterations in behavior, metabolism and health of offspring. Especially, maternal infections occurring during the third trimester of pregnancy interfere with the fundamental neurodevelopment events – cell proliferation and migration. Zinc supplementation however, has been shown to prevent endotoxin [lipopolysaccharide (LPS)]-induced teratogenicity and lipopolysaccharideinduced fetal growth restriction and demise through its anti-inflammatory properties by regulating TNF-a and interleukin (IL)–1b, NMDAR activity. The efficacy of zinc in ameliorating neurodegenerative effects caused in pups of LPS infected mothers has been least explored. Therefore, the purpose of this study is to investigate the effects of Zinc sulfate on the rat brain development exposed to endotoxemia during third trimester of pregnancy. Gender dependent behavioral, biochemical, histological and neurochemical effects induced by endotoxemia during third trimester of pregnancy were studied in developing rat brains Methods: Pregnant female rats were administered single dose of LPS (200mg/kg b.wt, i.p.) during third trimester of their pregnancy. Zinc supplementation was given through drinking water (75mg ZnSO4/liter deionized water) throughout pregnancy. Results: Following LPS injection in pregnant female rats, significantly altered levels of neurotransmitters and associated motor behavior dysfunction as well as cognitive decline have been observed in male as well as female pups. Whereas, supplementation with Zinc limited the alterations in behavioral parameters (Active passive avoidance, plus maze, 8 arm radial maze, actophotometer and rotarod) as well as significantly improved the level of neurotransmitters in prenatally exposed pups of both genders. However, antioxidant defence system was found to be excessively compromised in prenatally exposed female pups when compare to LPS treated

male pups as well as control pups. Conclusions: Hence, the study indicated LPS mediated toxicity in prenatally exposed rats are gender specific and supplementation during infection to LPS in pregnancy mitigated LPS-induced alterations.

P4-047

RESVERATROL ATTENUATES INSULIN RESISTANCE–ASSOCIATED COGNITIVE DEFICITS IN RATS

Anand Kamal Sachdeva, Kanwaljit Chopra, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Contact e-mail: [email protected] Background: A large body of evidence now suggests that Alz-

heimer’s is primarily a metabolic disease, which is characterized by glucose intolerance and CNS insulin resistance. It is accompanied by decreased expression of insulin, insulin receptor genes and impaired brain insulin signaling. Resveratrol is a natural polyphenol widely present in plants which has demonstrated neuroprotective effects in various preclinical and clinical studies. Thus, the present study was designed to elucidate the neuroprotective effect of resveratrol in an experimental paradigm of insulin resistanceinduced cognitive deficits in rats. Methods: Six-week-old male Wistar rats were fed with 15% fructose in drinking water for 24 weeks. Body mass, food and water intakes were measured regularly as well as plasma insulin, blood glucose, glycosylated heamoglobin, HOMA-IR, lipid levels and blood pressure were measured to ensure development of insulin resistance. Insulin resistance associated cognitive impairment was measured by using Morris water maze test (computer tracking using EthoVision software) and elevated plus maze on 24th week. Treatment with resveratrol (5, 10 and 20 mg/kg) was initiated after 6th week of fructose administration and continued till the end of study. Results: Insulin resistance was evident at 6th week and persisted till end of study (24th week) as demonstrated by significant increase in body weight, plasma insulin, blood glucose, glycosylated heamoglobin, HOMA-IR, blood pressure and a deranged lipid profile. Cognitive deficit was significantly evident at 24th week. Fructose-induced neuronal deficits were coupled with significant alterations in oxidative-nitrodative stress along with elevation of NF-kB and its downstream mediators as TNF-a, TGF-b1, caspase-3 and IL 1b levels. Resveratrol dosedependently ameliorated emergence of insulin resistance-induced memory impairment along with mitigation of oxido-nitrosative stress mediated alterations in cytokine levels. Conclusions: These results provide a novel insight into the neuroprotective effects of resveratrol and its possible therapeutic role in neuronal insulin resistance-induced memory impairment.

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CONVERGENT ANALYSIS OF ENDOPHENOTYPES IN PROGRESSIVE SUPRANUCLEAR PALSY

Mariet Allen1, Xue Wang1, Curtis S. Younkin1, Daniel Serie1, Zhifu Sun2, Jeremy D. Burgess1, Saurabh Baheti2, Naomi Kouri1, Thuy Nguyen1, Sarah Lincoln1, Kimberly G. Malphrus1, Minerva M. Carrasquillo1, Fanggeng Zou1, High-Seng Chai2, Melissa E. Murray1, Gerard D. Schellenberg3, Steven G. Younkin1, Julia E. Crook1, Tamas Ordog2, Yan W. Asmann1, Dennis W. Dickson1, Nilufer ErtekinTaner1, 1Mayo Clinic, Jacksonville, FL, USA; 2Mayo Clinic, Rochester, MN,

Poster Presentations: Wednesday, July 27, 2016 USA; 3University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: Progressive Supranuclear palsy (PSP) is a neurodegen-

erative parkinsonian disorder pathologically characterized by the presence of neurofibrillary tangles (NFT) and tau-positive glial lesions: tufted astrocytes (TA) and oligodendroglial coiled bodies (CB). Transcriptional regulation has been implicated as a likely disease mechanism at some of the disease risk loci identified by a genome-wide association study (GWAS). Genome-wide expression quantitative trait locus (eQTL) studies in the brains of PSP subjects, when combined with additional endophenotypes, may identify novel disease genes with an implied mechanism of action, important for future therapeutic targeting. Methods: Gene expression profiles were collected from temporal cortex for 2 cohorts of PSP samples (N: Cohort A ¼175, Cohort B ¼ 106), using the Illumina Whole-Genome DASL assay (WG-DASL). All subjects had available GWAS genotypes from one of two platforms (Illumina Human Hap300 or Illumina Human 660W-Quad). Probes that were detected in > 50% of the subjects were assessed. Cis-eQTL (gene +/-100kb) analysis was implemented in PLINK using linear regression, including appropriate covariates. Meta-analysis was performed using METAL. 43 subjects from expression cohort A also have DNA methylation measures collected using reduced representation bisulfite sequencing (RRBS). Neuropathological measures for the following four lesions: NFT, CB, TA and tau neuropil threads (TAUTH) are available for 251 of the subjects with expression measures. Results: The two expression cohorts had a total of 424,102 SNP-probe pairs in common (177,685 SNPs in-cis (+/-100kb) with 11,705 genes targeted using 14,880 probes). Meta-analysis identified 1,433 SNP probe pairs (341 unique genes) with a p-value < 1E-08. Gene Ontology enrichment analysis determined a significant enrichment of these genes within glutathione metabolism pathways (Bonferonni-adjusted p-value < 0.05). Additionally the PSP candidate gene MOBP, nominated by disease GWAS, has multiple cis-SNPs with a p<1E-08. Conclusions: We are pursuing the eQTL identified in this study for association with DNA methylation measures, neuropathological traits and linking these results to those of the PSP risk GWAS to identify significant eQTL enriched for PSP relevant variants. These studies will nominate regulatory genetic changes as the potential culprit for some of the PSP risk loci and can uncover novel biological pathways implicated in PSP.

P4-049

SERIAL CHANGES OF DIFFUSION-WEIGHTED IMAGING (DWI) AND BRAIN COMPUTED TOMOGRAPHY (B-CT) IN A PATIENT WITH CREUTZFELDT–JAKOB DISEASE WITH V180I MUTATION

Kyung-Ho Choi, Seoul National University Hospital, Seoul, Republic of Korea. Contact e-mail: [email protected] Background: Creutzfeldt-Jakob disease (CJD) is the most common phenotype of human prion disease with a prevalence of 1 to 1.5

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cases per million person. CJD was classified as sporadic, acquired and familial (inherited) forms and 10 to 15% of them are estimated to be familial CJD case. To date, more than 55 mutations in the human PrP gene (PRNP) have been reported, whose phenotypic variability may be affected by the specific PRNP mutation with a polymorphism at codon 129.CJD with a point mutation of valine to isoleucine at codon 180 (V180I) of PRNP is a type of familial CJD with rare mutations. Methods: Here, we report a biopsy case of CJD with V180I mutation of slow progression and long duration with variably protease-sensitive prionopathy. We report serial changes of diffusion-weighted imaging (DWI) and brain computed tomography (B-CT) in a patient with Creutzfeldt–Jakob disease with V180I mutation. Results: DWI abnormalities in our patient were more predominantly observed in the right cerebral cortex than right basal ganglia. Hemilateral abnormalities progressed over 4 months to involve the contralateral side with increasing DWI signals. At 8 years, she was still alived. B-CT were observed diffuse cerebromalacia. Conclusions: We report that CJD with V180I are very slow progression and long duration.

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TWO NOVEL GRN MUTATIONS IN KOREAN PATIENTS DIAGNOSED WITH EARLY ONSET ALZHEIMER’S DISEASE

Eva Bagyinszky1, Vo Van Giau2, Minjung Wang3, Young Ho Park3, Jae Won Jang4, So Young Park5, Young Chul Youn6, Seong Soo An2, SangYun Kim3,7,8, 1Gachon University, Seongnam, South Korea; 2Gachon University, Seongnam, South Korea; 3Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; 4 Kangwon National University, Chuncheon, Republic of Korea; 5Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam, South Korea; 6Chung-Ang University Hospital, Seoul, South Korea; 7Seoul National University Bundang Hospital, Seongnam, South Korea; 8Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Contact e-mail: [email protected] Background: GRN or PGRN gene is one of the main causative gene of frontotemporal dementia, where several pathogenic or probably pathogenic mutations have been described. However, significant pathological overlap could be found between FTD and Alzheimer’s disease. Methods: In our studies, we designed a gene panel for 50 neurodegenrative disease causative and risk factor genes, and performed NGS for these coding regions. Mutations were verified by automated Sanger sequencing. In silico predictions were performed for the missense variants to estimate their role in different disorders. Results: We discovered two novel GRN mutations, S40N and R564C in exon 1 and exon 12, respectively. Both carrier patients were in their 60s, and diagnosed with EOAD. SIFT and PolyPhen suggested that these mutations could be involved in disease. 3D modeling will be performed on them in the future. Conclusions: Several patients with FTD were misdiagnosed as AD. A complex genetic screening could improve the diagnosis and the therapies. It also could help to understand the disease-associated pathways.