1. Kei Cho (Professor of Neuroscience) Henry Wellcome LINE and MRC Centre for Synaptic Plasticity How does Aβ influence synaptic plasticity? How does Aβ regulate postsynaptic proteins? Synaptic Plasticity: Pathways towards and away from Amyloid-  peptide-mediated synaptic dysfunction MRC Medical Research Council Centre for Synaptic Plasticity

2. Synaptic Plasticity and Alzheimer’s Disease Cerebral elevation and accumulation of A  1-42 peptide in many aspects of AD mediated pathogenesis. Oligomeric forms of A  1-42 in the extracellular space correlates with cognitive decline and synaptic alterations ( impairment of LTP, inflammation, fibrillization ) Synaptic Transmission

3. The role of A  in synaptic plasticity AAAA LTP LTD

4. Intracellular Extracellular ? A  oligomers Plasma Membrane Signal cascades   ? Output Neurotoxicity, Cell death, Atrophy, Synaptic dysfunction Target and Strategy Using a combination of biochemistry, molecular biology and electrophysiology, the project will explore whether soluble A  regulates enzymes and postsynaptic protein-protein interactions involved in LTP and LTD. Molecules of interest include PSD-95, GRIP1, PICK1, AMPARs, caspase and neuronal calcium sensors.

5. Method & Application Dominant-negative shRNAi Interfering-peptide Overexpression Antibody Pharmacology Target Assays Synaptic Transmission Synaptic Plasticity (LTP/LTD) Morphological Plasticity (multi-photon imaging) Protein-protein interaction (Co-IP/GST-Pull down/Western- blot) Target Protein RNAi FluorescenceMarker Two-Photon image: Electrophysiology: LTP/LTD, Basal synaptic transmission (AMPAR and NMDAR-mediated Synaptic current) Approach 1 Dendritic spine morphology, Spine / Presynaptic bouton calcium imaging, Time-lapse imaging Approach 2 A  oligomers Protein Assay Brain slice culture with A 

6. Recent Relevant Publications from the Cho and Collingridge Groups LTP inhibits LTD in the hippocampus via regulation of GSK3beta (2007, Neuron 53, 703-717) Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95 (2007, Neuron 56, 488-502) An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity (2008, Neuron, 57, 872-882) Metabotropic glutamate receptor- mediated LTD involves two interacting Ca 2+ sensors, NCS-1 and PICK1 (2008, Neuron, 60, 1095-1111) Postsynaptic neuron

7. Molecule to Cognition Unit Satellite Research Facility Molecule to Cognition Unit Consortium: Graham Collingridge, Bong-Kiun Kaang, Sang-Jeong Kim and Min Zhou, Kei Cho (Adjunct Faculty)

8. United Kingdom Canada SPINE (Synaptic Plasticity & Integrative Neuroscience and Endocrinology), Bristol Physiology, Univ. of Toronto  MRC Centre for Synaptic Plasticity, Univ. of Bristol  Henry Wellcome Laboratories for Integrative Neuroscience & Endocrinology, Univ. of Bristol Molecule to Cognition Unit Brain & Cognitive Sciences, SNU, Korea

9. Henry Wellcome LINE Alzheimer’s Disease Synaptic Plasticity & Repair Molecular Biology & Stem Cell Biology MRC Centre for Synaptic Plasticity (23PIs) SPINE, Bristol Stress & Endocrinology

10. Multi-Photon Imaging Technique Multi-photon microscopy enables high resolution imaging in brain tissue (e.g. slices and in vivo). Confocal microscopy is limited to thin tissue preparations (cell cultures or organotypic slices) 1  m High resolution multi-photon image: dendrite with spines Single-Photon Multi-Photon

11. Not Just Experiment but also……..

12. Molecule to Cognition Unit Satellite Research Facility ‘Best Regards’ to All of You from Kei’s Lab Plus Me!