The Molecular Imaging Unit focuses on the visualization of Alzheimer’s disease (AD) and Parkinson's disease (PD) related changes in model systems using a variety of light-microscopy techniques. 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.
1. To investigate proteopathic lesions and associated pathologies in organotypic slice cultures and in vivo in mouse brain.
2. To study microglial behavior in living cultures and brain, both in the context of normal aging and in models of neurodegeneration.
3. To associate the structure of misfolded proteins to disease pathogenesis via spectral changes of amyloid-sensitive dyes.
In order to reach those objectives, we use organotypic slice cultures and a variety of genetically modified mouse models for labeling specific cell populations, by endogenously expressing fluorescent proteins. We use a wide range of light microscopy techniques, mostly multi-photon microscopy, combined with custom-built apparatuses for long-term imaging and with stereological and 5D analyses.
Through a series of in vivo experiments, whereby individual microglia cells were imaged longitudinally in the living mouse brain, we have established that these are long-lived cells with an expected lifetime of more than 15 months. Consistently, proliferation of resident neocortical microglia under homeostatic conditions was low. In contrast, we found that microglial proliferation in a mouse model of ß-amyloidosis was increased several-fold. 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 Neurosci. 2017).
In a more recent application we have adopted our newly developed slice repositioning system for long-term imaging of cultured human adult brain tissue originating from resection surgery (collaboration with H. Koch, Department of Epileptology) (Schwarz et al., eLife 2019).
Although the molecular architecture of proteopathic lesions shares a common amyloid structure, individual lesions exhibit conformational variations that were shown by our group to be distinguished, using conformation-sensitive amyloid-binding dyes (LCOs). 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 Aß-amyloid among individuals and in etiologically distinct subtypes of AD and justify further studies to assess putative links between Aß conformation and clinical phenotype (Rasmussen et al., PNAS 2017).
Schwarz N, Uysal B, Welzer M, Bahr JC, Layer N, Löffler H, Stanaitis K, Pa H, Weber YG, Hedrich UB, Honegger JB, Skodras A, Becker AJ, Wuttke TV, Koch H (2019) Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease. eLife 8. pii:e48417
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)
Center of Neurology
Hertie Institute for Clinical Brain Research
Department Cellular Neurology
Phone: +49 (0)7071 29-87607
Fax: +49 (0)7071 29-4521