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Project Co-ordinator:

Prof. Leszek Kaczmarek
http://neurogene.nencki.gov.pl
l.kaczmarek@nencki.gov.pl
Nencki Institute
Warsaw, POLAND

 

Project Manager:

Ms. Marta Rucinska
m.rucinska@nencki.gov.pl
Nencki Institute
Warsaw, POLAND

 

Recruitment Co-ordinator

Prof. Alexander Dityatev
alexander.dityatev@dzne.de
Deutsches Zentrum fur
Neurodegenerative Erkrankungen
Magdeburg, GERMANY

 

Training Co-ordinator

Prof. Robert Pawlak
R.Pawlak@exeter.ac.uk
University of Exeter Medical School
Exeter, UK

ESR9:    APP ectodomain and structural plasticity of dendritic spines (lead: DZNE-2b, partners: NENCKI, DZNE-2a, ETEC)

Elena Montagna

elena.montagna@med.uni-muenchen.de

Elena.jpg

 

 

 

 

 

 

 

 

 

Many evidences support the role of APP in structural plasticity (Priller et al., 2006; Tyan et al., 2012; Lee et al., 2010 ) and recent data also suggest a role in the regulation of astrocytic D-serine homeostasis (Zou et al., 2016), as well as astrocytic calcium homeostasis and ATP production (Hamid et al., 2007; Linde et al., 2011).Aim of this project is to elucidate the physiological role of APP full length and its structural domains with particular focus on synaptic plasticity as well as on astrocytic calcium dynamics.To address the question of spine dynamics, both spine density and plasticity of different APP transgenic mouse models have been investigated. On one hand the use of conditional APP KO (APP flox mice crossed with Slick V mice) (Mallm et al., 2010; Young et al., 2008) allows to investigate the consequences on spine density and morphology of a post-synaptic lost of APP on a small subset of neurons.On the other hand investigating spine dynamics on APPΔCT15 (Ring et al., 2007) by the use of two photon in vivo microscopy allows to determine whether the APP ecto-domain is crucial for spine plasticity.Interesting spine density of conditional APP KO mice, analysed by confocal microscopy, is reduced if compare to control mice, thus suggesting a fundamental function for APP in maintaining dendritic spines. Furthermore in vivo investigation of spine plasticity on APPΔCT15  revealed the crucial role of APP ecto-domain for constituitive and adaptive spine plasticity.As our recent findings pointed out APP seems to play a role, not only on neuron plasticity but on astrocyte functions too (Zou et al., 2016); thus most likely influencing neuron plasticity too.Therefore second part of my project is the in vivo investigation of astrocytes activity by the combination of astrocytic calcium indicators and two-photon in vivo imaging in mice that lack of APP. Preliminary data revealed an alteration of calcium dynamics in astrocytes of the somatosensory cortex of APP KO mice. However the molecular mechanism behind these alteration need to be further elucidate. Our suggested hypothesis is a possible impairment in mitochondria morphology and functionality in APP KO mice, as suggested from some recent studies (Zhang et al., 2015; Wang et al., 2016), thus resulting in altered calcium dynamics.

For more information about research in the group, please see the following recent papers:

Burgold, S.; Bittner, T., Dorostkar, M.M.; Kieser, D.; Fuhrmann, M.; Mitteregger, G.; Kretzschmar, H.; Schmidt, B.; Herms, J. (2011) In vivo multiphoton imaging reveals gradual growth of newborn amyloid plaques over weeks. Acta Neuropathol. 121(3):327-35.

Bittner, T; Fuhrmann, M.; Burgold S.; Ochs S.; Hoffmann, N.; Mitteregger, G.; Haass, C.; LaFerla, F.M.; Kretzschmar, H.A.; Herms, J. (2010) Multiple Events lead to dendritic spine loss in triple transgenic Alzheimer’s disease mice. PLoS One. 5(11):e15477

Fuhrmann, M.; Bittner, T.; Jung, C.K.E.; Burgold, S.; Page, R.M.; Mitteregger, G.; Haass, C.; LaFerla, F.M.; Kretzschmar, H.A.; Herms, J. (2010) Microglia CX3CR1 knockout prevents neuron loss in an Alzheimer`s disease mouse model. Nature Neurosci. 13:411-413

Bittner T., Fuhrmann M., Burgold S., Jung C.K.E., Volbracht C., Steiner H., Mitteregger G., Kretzschmar H. A., Haass C., Herms J. (2009) Gamma-Secretase inhibition reduces spine density in vivo via an APP-dependent pathway. J. Neurosci. 29:10405-10409.

The German Center for Neurodegenerative Diseases (DZNE) is a center of excellence within the Helmholtz Association that performs translational research on Neurodegenerative Diseases. The DZNE Munich (http://www.dzne.de/en/sites/munich.html) offers an excellent infrastructure in a unique research environment, with combination of animal and clinical research and in close collaboration with researchers from the Munich cluster of system neurology SyNergy (http://www.synergy-munich.de/index.html).

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In vivo Imaging of the evolving damage on a nerve cell process over 60 days in a transgenic mouse model of Alzheimer`s desease.