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Molecular Imaging Unit

The Molecular Imaging Unit focuses on the visualization of Alzheimer’s disease (AD) and Parkinson's disease (PD) related changes in model systems using in vivo multiphoton microscopy. A solid knowledge of the dynamics of proteopathic lesions and associated neurodegeneration and neuroinflammation is essential for the understanding of disease pathomechanisms and also critical for the interpretation of brain imaging in clinical studies.

Main objectives
Recent results
Staff
Publications

1. To investigate proteopathic lesions and associated pathologies in organotypic slice cultures and in vivo in mouse brain.

2. To characterize novel amyloid-binding dyes with respect to their staining properties of different amyloid conformations.

3. To study microglial behavior in living cultures and brain, both in the context of normal aging and in models of neurodegeneration.

To this end, we use organotypic slice cultures and a variety of transgenic mouse models of cerebral amyloidoses in combination with endogenously fluorophore-labeled microglia and/or neuronal subpopulations. In vivo examination is performed using multiphoton microscopy combined with a set of advanced imaging tools for stereological and 5D analysis of the morphological datasets.

To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. To this end, we have genetically labelled individual microglia in living mice and used our multiphoton imaging system with custom-made head and repositioning tools to previously imaged areas (Hefendehl et al., J Neurosci Methods 2012). We found a median lifetime of microglia of 15 months and thus discovered a remarkable longevity of microglia (Füger et al., Nature Neuroscience 2017). Consistently, proliferation of resident neocortical microglia under homeostatic conditions was low. In contrast, we found that microglial proliferation in a mouse model of β-amyloidosis was several-fold increased. The persistence of individual microglia throughout the mouse lifespan now provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases (Füger et al., Nature Neuroscience 2017).

Although the molecular architecture of proteopathic lesions share a common amyloid structure, individual lesions exhibit conformational variations that cannot be distinguished using classical amyloid-binding dyes. We have used a novel class of amyloid-binding dyes (LCOs) that cross the blood brain barrier and stain Aβ deposits and tau inclusions. When bound to amyloid structures LCOs exhibit a conformation-dependent emission spectra that allows spectral discrimination of structurally different amyloid lesions (Wegenast-Braun et al., Am J Pathol 2012). We have now analyzed the LCO-stained amyloid deposits in postmortem brain of familial or sporadic Alzheimer's disease (AD). Remarkably, the LCO amyloid spectra differed significantly among some of the familial and subtypes of sporadic AD (e.g. posterior cortical atrophy subtype of AD). These findings indicate heterogeneity in the molecular architecture of Aβ-amyloid among individuals and in etiologically distinct subtypes of AD and justify further studies to assess putative links between Aβ conformation and clinical phenotype (Rasmussen et al., PNAS 2017)

Contact: Angelos Skodras, Bettina Wegenast-Braun

 

 


 
Name
Department
Phone
Email
 Bernadette Dahl
Bernadette Dahl Master Student
Molecular Imaging
07071 29-81945 
Dr. Deborah Kronenberg-Versteeg
Dr. Deborah Kronenberg-Versteeg PostDoc
Molecular Imaging
07071 29-87596 
Dr. Angelos Skodras
Dr. Angelos Skodras Group Leader
Molecular Imaging
07071 29-87607 
Dr. Bettina Wegenast-Braun
Dr. Bettina Wegenast-Braun Group Leader
Molecular Imaging
07071 29-87607 
 Marc Welzer
Marc Welzer Master Student
Molecular Imaging
07071 29-81945 

Rasmussen J, Mahler J, Beschorner N, Kaeser SA, Hasler LM, Baumann F, Nystrom S, Portelius E, Blennow K, Lashley T, Fox NC, Sepulveda-Falla D, Glatzel M, Oblak AL, Ghetti B, Nilsson KPR, Hammarstrom P, Staufenbiel M, Walker LC, Jucker M (2017) Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. Proc Natl Acad Sci USA 114: 13018-23 (Abstract)

Füger P, Hefendehl JK, Veeraraghavalu K, Wendeln AC, Schlosser C, Obermuller U, Wegenast-Braun BM, Neher JJ, Martus P, Kohsaka S, Thunemann M, Feil R, Sisodia SS, Skodras A, Jucker M (2017) Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging. Nat Neurosci 20: 1371-6 (Abstract)

Hefendehl JK, Neher JJ, Sühs RB, Kohsaka S, Skodras A, Jucker M (2014) Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13:60-9 (Abstract)

Wegenast-Braun BM, Skodras A, Bayraktar G, Mahler J, Fritschi SK, Klingstedt T, Mason JJ, Hammarstrom P, Nilsson KP, Liebig C, Jucker M (2012) Spectral discrimination of cerebral amyloid lesions after peripheral application of luminescent conjugated oligothiophenes. Am J Pathol 181:1953-60 (Abstract)

Hefendehl JK, Milford D, Eicke D, Wegenast-Braun BM, Calhoun ME, Grathwohl SA, Jucker M, Liebig C (2012)  Repeatable target localization for long-term in vivo imaging of mice with 2-photon microscopy. J Neurosci Meth 205:357-63 (Abstract)

Hefendehl JK*, Wegenast-Braun BM*, Liebig C, Eicke D, Milford D, Calhoun ME, Kohsaka S, Eichner M, Jucker M (2011) Long-term in vivo imaging of β-amyloid plaque appearance and growth in a mouse model of cerebral β-amyloidosis. J Neuroscience 31:624-9 (Abstract)

Contact
Dr. Angelos Skodras angelos.skodrasdzne.de Address

Center of Neurology
Hertie Institute for Clinical Brain Research
Department Cellular Neurology

Otfried-Müller-Straße 27
72076 Tübingen

Phone: +49 (0)7071 29-87607
Fax: +49 (0)7071 29-4521