Professor Gunnar K. Gouras, Lund University, Lund, Sweden
ESR1, Determine the molecular and cellular mechanism of Aβ induced synaptic dysfunction

Professor Jia-Yi Li, Lund University, Lund, Sweden
ESR2, Determine molecular mechanisms of synaptic dysfunction in models of Parkinson’s disease

Professors Gunnar K. Gouras and Jia-Yi Li, Lund University, Lund, Sweden
ESR3, Unravel mechanisms of and protection against neuron-to-neuron propagation of misfolded proteins in Alzheimer’s disease and Parkinson’s disease

Professor Maria Grazia Spillantini, University of Cambridge, Cambridge, UK
ESR4, From the gut to the brain: pattern and mechanisms of α-synuclein pathology spreading in a new transgenic mouse model with α-synuclein in the gut

Professor Daniel Choquet, Centre National de la Recherche Scientifique, Bordeaux, France
ESR5, Molecular mechanisms that link mutant huntingtin to defective plasticity of glutamatergic synaptic transmission

Professor David Perrais, Centre National de la Recherche Scientifique, Bordeaux, France
ESR6, Linking dendritic membrane recycling and synaptic function in Alzheimer’s disease

Professor Tiago Outeiro, University Medical Center Goettingen, Göttingen, Germany
ESR7, The mechanisms and consequences of protein release and uptake at the synapse: towards the understanding of the relevance of the spreading of pathology in neurodegeneration

Professor Jochen Herms, German Center for Neurodegenerative Diseases (DZNE) & LMU Munich, Munich, Germany
ESR8, Mechanisms of synaptic dysfunction following the accumulation of a-synuclein
ESR9, Characterisation of axonal and synaptic pathology at amyloid beta plaques

Professors Patrick Aebischer, Brian McCabe and Bernard Schneider, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
ESR10, Molecular mechanisms to reinforce synaptic connections in the context of amyotrophic lateral sclerosis caused by SOD1 mutations

Centre National de la Recherche Scientifique, Bordeaux, France and QuantaCell, Pessac, France
ESR11, Image restoration and image analysis for multispectral imaging on biological samples

Umecrine AB, Umeå, Sweden
ESR12, Modulators of GABA-A receptor function as AD treatment and synaptic protection


ESR1, Determine the molecular and cellular mechanism of Aβ induced synaptic dysfunction

Using advanced imaging, biophysical and biochemical methods to determine the pathway(s) of amyloid induced synapse dysfunction in relation to amyloid aggregation in primary neuron and brain models of Alzheimer’s disease. Emphasis will be on the pre- and post-synaptic cellular mechanisms whereby β-amyloid and the amyloid precursor protein induce the earliest alterations in synapses and in endosomes occurring in the disease, as well as their therapy-relevant modulation.

 

ESR2, Determine molecular mechanisms of synaptic dysfunction in models of Parkinson’s disease

The goal of the project is to study molecular mechanisms of impaired synaptic plasticity in Parkinson’s disease, particularly in α-synuclein overexpression and the protein aggregation models. Structurally, we will determine the interaction between microglia and neuronal components (axon, dendritic spines and synapses) and dendritic spine remodeling with two-photon laser scanning and super-resolution microscopes. Molecularly, we will study mechanisms of α-synuclein protein aggregation and propagation on AMPA receptor dynamics in glutamatergic synapses with live-cell imaging and super-resolution imaging.

 

ESR3, Unravel mechanisms of and protection against neuron-to-neuron propagation of misfolded proteins in Alzheimer’s disease and Parkinson’s disease

The goal of the project is to use a combination of cutting edge imaging technologies (e.g. live-cell, time-lapsing imaging, super-resolution microscopy and two photon in vivo imaging) to test how synaptic activity effects the propagation of Aβ and tau, particularly to uncover the cellular mechanisms of, and potential interactions between, the release and uptake of these proteins at synapses, and to determine their role of synaptic activity (including activation of specific neurontransmitter receptors) in neuron-to-neuron spread of Aβ and tau in primary neurons and in vivo models of AD, and to study the mechanisms whereby antibodies can modulate cell-to-cell propagation and synapse protection.

 

ESR4, From the gut to the brain: pattern and mechanisms of α-synuclein pathology spreading in a new transgenic mouse model with α-synuclein in the gut

A new transgenic mouse expressing truncated human alpha-synuclein in the gut is now available. The aim of the project is to investigate if and how alpha-synuclein pathology spreads from the gut to the brain and the role of synaptic contact in this process. Techniques of molecular biology, immunohistochemistry, biochemistry and imaging will be used.

 

ESR5, Molecular mechanisms that link mutant huntingtin to defective plasticity of glutamatergic synaptic transmission

The goal of the project is to define the mechanisms that cause defective synaptic plasticity at excitatory synapses in mice models of Huntington’s disease (HD). By using a combination of innovative super-resolution imaging in live neurons, electrophysiology, cell biology and novel chemical biology tools, we will identify the key glutamate receptor trafficking steps that are altered in HD and will determine the molecular mechanisms responsible for altered synaptic function.

 

ESR6, Linking dendritic membrane recycling and synaptic function in Alzheimer’s disease

The objective of the project is to dissect with advanced imaging and synaptic physiology techniques in models of Alzheimer’s disease (AD) how alteration of dendritic membrane recycling affects amyloid peptide production, the trafficking of AMPA receptors, synaptic transmission and synaptic plasticity. In particular, the project will investigate the role of the retromer complex in the control of the recycling of a number of cargo proteins such as APP and various neuronal receptors as many genes of the retromer complex have been linked to higher susceptibility to AD.

 

ESR7, The mechanisms and consequences of protein release and uptake at the synapse: towards the understanding of the relevance of the spreading of pathology in neurodegeneration

 

ESR8, Mechanisms of synaptic dysfunction following the accumulation of α-synuclein

The goal of the project is to define the mechanisms that cause dendritic spine loss due to α-synuclein aggregation in the cerebral cortex of mouse models of Parkinson’s disease and related diseases as well as human tissue samples. By the use of cutting edge technologies including in vivo two-photon imaging, high-resolution imaging, in vivo electrophysiology as well as MALDI-Imaging in human tissue samples we aim to identify the signal cascades that cause altered synaptic plasticity and stability throughout the accumulation of α-synuclein at cortical synapses.

 

ESR9, Characterisation of axonal and synaptic pathology at amyloid beta plaques

The goal of the project is it to define the cascade of events that cause axonal dysfunction and synaptic pathology in the vicinity of amyloid plaques in mouse models of Alzheimer’s disease. For this purpose we apply recently established approaches of correlative in vivo two-photon imaging/focus ion beam scanning electronmicroscopy (FIB-SEM) of axonal changes at plaques. We aim to define the cascade of events that cause axonal dysfunction and the accumulation of various cargos within axons as well as their consequence for synaptic plasticity and stability.

 

ESR10, Molecular mechanisms to reinforce synaptic connections in the context of amyotrophic lateral sclerosis caused by SOD1 mutations

The objective of the project is to determine the molecular mechanisms, which control the maintenance of the synaptic connections both in the spinal cord and at the level of the neuromuscular junctions. These mechanisms will be explored using both fly and mouse models of amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations. The project is based on state-of-the-art techniques to genetically modify in vivo neurons and glial cells using viral vector technologies, as well as quantify synaptic contacts and function in models of ALS. The long-term goal is to establish novel targets for gene therapy against ALS.

 

ESR11, Image restoration and image analysis for multispectral imaging on biological samples
The aim of the project is to develop analysis techniques applicable to multi-spectral imaging to separate a large number of fluorescent probes using unmixing strategies. The goal is to be able to analyze separated channels and to detect FRET events (fluorescence resonance energy transfer). The application will be done on SPT (single particle tracking) data in neuron’s synapses and in brain tissues. The sources code will use openCV C++ and will be packaged into an easy to use software application, and it will be compatible industry standards.

 

ESR12, Modulators of GABA-A receptor function as AD treatment and synaptic protection

To test if decline in cognitive function in transgenic Alzheimer’s disease (AD) mice can be hindered by treatment with GABA-A modulating steroid antagonist (GAMSA). Hippocampus brain tissue from GAMSA and placebo treated transgenic AD mice will be investigated for memory, intrasynaptic Aβ and markers of reduced synaptic survival and function using already developed and published techniques.
Umecrine AB is a spin off from research at Umeå University, Sweden. The company has patents with compounds to be investigated for synaptic saving in AD mice. Some compounds have already showed proof-of-concept in animal and human models with all regulatory authorises approvals.

 

 

EU Horizon 2020 Marie Sklodowska-Curie Actions

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 721802.