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  Glial and vascular contributions to neurodegenerative diseases
  AD models, decreasing EAAT2 expression enhances, while decreasing EAAT2 expression slows disease progression. These observations indicate EAAT2 as a novel drug target in AD.
Methods: Here, we describe an assay for drugs that activate EAAT2 in glutamate uptake. In the assay, EAAT2 is reconstituted in liposomes and glutamate uptake is measured with red fluorescent Oxonol VI light emission.
Discussion: In astrocyte-neuron cell culture, the EAAT2 activating drugs are studied for specificity, efficacy, safety and neuroprotection against glutamate neurotoxicity.
  PP27
Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s Disease
Mridula Bhalla1,2, Yeonha Ju1,2, Seung Jae Hyeon3, Ju Eun Oh4, Seonguk Yoo4, Uikyu Chae3, Jea Kwon1,5, Wuhyun Koh1, Jiwoon Lim1,2, Yongmin Mason Park1,2, JungHee Lee6, Il Joo Cho3,7,8, Hyunbeom Lee4, Hoon Ryu3, C Justin Lee1,2
1Center for Cognition and Sociality, Institute For Basic Science (IBS), Daejeon, South Korea, 2IBS School, University of Science and Technology (UST), Daejeon, South Korea, 3Brain Science Institute (BSI), Korea Institute of Science and Technology (KIST), Seoul, South Korea, 4Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul, South Korea, 5Korea University-Korea Institute of Science and Technology, Graduate School of Convergence Technology, Korea University, Seoul, South Korea, 6Boston University Alzheimer’s Disease Research Center and Department of Neurology, Boston University School of Medicine, Boston, USA, 7School of Electrical and Electronics Engineering, Yonsei University, Seoul, South Korea, 8Yonsei-KIST Convergence Research Institute, Yonsei University, Seoul, South Korea
   PP29
Chronic effects of a low glycemic index diet in neuroinflammation in the 5xFAD mouse model of Alzheimer's disease
Ioannis Dafnis1, Christina Mountaki1, Eleni Fanarioti2, Dimitrios C Mastellos1, Michalis Karvelas3, Vaios T Karathanos4, Athina Tzinia1, Catherine R Dermon2,
Angeliki Chroni1
1National Center For Scientific Research Demokritos, Athens, Greece, 2University of Patras, Patras, Greece, 3Agricultural Cooperatives' Union of Aeghion, Aeghion, Greece, 4 Harokopio University, Athens, Greece
 Background: Alzheimer’s disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (Aβ) plaques and significant progressive memory loss. In AD, astrocytes are proposed to take up and clear Aβ plaques. However, how Aβ induces pathogenesis and memory impairment in AD remains elusive. Materials and Methods: The presence of urea cycle in primary astrocyte cultures and human AD patient astrocytes was evaluated using Next- Generation Sequencing. Metabolite analysis, molecular assays and a newly developed in vivo sensor were used to study the levels of urea cycle metabolites in healthy and AD-like conditions. Mouse model of AD was used to study the effect of gene silencing of key urea cycle enzymes on astrocyte reactivity, memory and Aβ plaque clearance. Results: Normal astrocytes show non-cyclic urea metabolism, whereas Aβ-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulation of aspartate, ammonia, urea, and side- product putrescine. Pharmacological inhibition and gene-silencing of astrocytic ornithine decarboxylase-1 (ODC1), the enzyme facilitating ornithine-to-putrescine conversion, boosts the urea cycle and eliminates production of GABA, ammonia and H2O2 from putrescine. This facilitates recovery from reactive astrogliosis and memory impairment in a mouse model of AD. Additionally, we find that long- term genetic silencing of ODC1 in AD mouse brains promotes Aβ clearance while switching amyloid precursor protein (APP) processing from amyloidogenic to non-amyloidogenic. Elevated levels of astrocytic proBDNF suggest the conversion of reactive astrocytes to active, synapse-promoting astrocytes [1].
Discussion: Our findings implicate that astrocytic urea cycle exerts opposing roles of beneficial Aβ detoxification and detrimental memory impairment in AD [2]. Altogether, we propose ODC1-inhibition as a promising therapeutic strategy against AD to reduce reactive gliosis, facilitate removal of toxic molecules and prevent memory loss [3].
Background: Glutamate is the major synaptic signaling molecule of neurons, essential in learning, memory and cognition. As soon as the glutamate signaling starts, it is stopped by astrocytes (which cover synapses), which take up and clear glutamate from the synapses. This prevents extended signaling and glutamate neurotoxicity, which can impair neurotransmission, and lead to synapse loss and neuron cell death. Astrocytes express EAAT2 (excitatory amino acid transporter-2), the major glutamate transporter and 1% of brain protein. In Alzheimer’s disease (AD), astrocytes express less EAAT2. In experimental mouse
Background: Alzheimer’s disease (AD) is associated with brain amyloid‐β (Aβ) peptide accumulation and neuroinflammation. Currants, a low glycemic index dried fruit, and their components display pleiotropic neuroprotective effects in AD.
Materials/methods: We administered diet containing 5% Corinthian currant paste (CurD), sugar-matched diet containing 3.5% glucose/ fructose (GFD) or control diet (ConD) in one-month-old 5xFAD mice for 1, 3 and 6 months and examined the diet effects on Aβ levels and neuroinflammation.
Results: No change in serum glucose or insulin levels was observed among the three groups. CurD administered for 3 months reduced brain Aβ42 levels in male mice as compared to ConD and GFD, but after 6 months, Aβ42 levels were increased in mice both on CurD and GFD as compared to ConD. CurD for 3 months also reduced TNFα and IL-1β levels in male and female mouse cortex homogenates compared to ConD and GFD. However, after 6 months, TNFα levels were increased in cortex homogenates of mice both on CurD and GFD as compared to ConD. A similar pattern was observed for TNFα-expressing cells, mostly co-expressing the microglial marker CD11b, in mouse hippocampus following 3 and 6 months of diet. IL-1β levels were similarly increased in the brain of all groups after 6 months. Furthermore, a time dependent decrease of secreted TNFα levels was found in BV2 microglial cells treated with currant phenolic extract as compared to glucose/fructose solution.
Conclusion: Our findings suggest that a short-term currant consumption reduces neuroinflammation in 5xFAD mice, but longer- term intake enhances neuroinflammation, that could be attributed to diet’s sugar content, despite the lack of effect on serum glucose and insulin levels.
Funding: Project “CUReANT” (T1EDK-04290, MIS 5030607), Research- Create-Innovate action co‐financed by the EU and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation (NSRF 2014-2020).
  PP28
Targeting astrocyte glutamate transporter EAAT2 in Alzheimer's disease
Lloyd Tran1, Markku Kurkinen
1Biomed Industries, Inc., San Jose, USA
 62 • ISMND 2022









































































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