The molecular imaging group focuses on the visualization of Alzheimer’s disease (AD) related changes in the brain of mouse models using in vivo multiphoton microscopy. In vivoimaging of individual AD lesions is essential for a better understanding of their functional impact but also enhances the translational interpretation of amyloid imaging in humans. Moreover, in vivo monitoring of AD lesions and associated gliosis as well as neurodegeneration provides a powerful tool to monitor in vivo therapeutic preclinical strategies.
1. To study in vivo the development of β-amyloid (Aβ) lesions and associated pathologies in the mouse brain.
2. To study novel amyloid-binding dyes with respect to their blood brain barrier penetrance and staining characteristics of β-amyloid versus tau lesions.
3. To study in vivo microglial behavior with normal aging and in mouse models of neurodegeneration.
To this end, we use a variety of transgenic mouse models of cerebral amyloidoses and tauopathies also 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.
We have used multiphoton in vivo imaging to study Aβ plaque formation in the brains of APPPS1 transgenic mice. By using a newly designed head fixation system (Hefendehl et al., J Neurosci Methods 2012) with automatic rapid finding of previously marked areas we have successfully identified newly appearing amyloid deposits and tracked single amyloid plaques for up to 6 months. Results revealed that newly formed amyloid plaques develop in the APPPS1 transgenic mouse model at an estimated rate of 35 per mm3 neocortical volume per week at the age of 4-5 months. At later time points, i.e. with increasing cerebral β-amyloidosis, the number of newly formed plaques declined in comparison to the early phases of amyloid deposition. Both newly formed and existing plaques grew with a similar weekly increase of 0.3 μm in radius over the entire imaging period (Hefendehl et al., J Neuroscience 2011).
In a previous multiphoton in vivo study we could demonstrate that local resident microglia rapidly react to Aβ plaque formation by extending processes and subsequently migrating toward plaques. Amyloid plaque associated microglia somata remained spatially stable for weeks to months. Far from adopting a more static role plaque-associated microglia retained rapid processes and membrane movement at the plaque/glia interface (Bolmont et al., J Neuroscience 2008).
These results suggest that amyloid plaque formation is a spontaneous process likely dependent on the local concentration of Aβ, which in turn is in dynamic equilibrium with the insoluble Aβ associated with the amyloid plaques. Once aggregation has started microglia move towards the amyloid, adopt a phagocytic morphology, but are unsuccessful in clearing the amyloid. A solid knowledge of the dynamics of cerebral β-amyloidosis is essential for the understanding of AD pathogenesis and the interpretation of amyloid-imaging in AD clinical studies. The understanding of the role of microglia, as the brains’ main immune cell capable of phagocytosis, provides new possible targets for therapeutic intervention.
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)
Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M, Calhoun ME (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neuroscience 28:4283-92 (Abstract)