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D. HAVAS1, J. PINDJAKOVA, I. MORGANSTERN1, T. HANANIA1


1PsychoGenics, Inc., Paramus, NJ, USA


Objectives: Today’s knowledge about microglial morphology and activation states vastly relies on in vitro cell culture experiments. Criticism to those theories rose steadily during the last decade, especially when looking at post mortem conditions in brain tissue. In Alzheimer’s disease (AD) animal models we see microglia clustering around amyloid plaques, de-ramifying and with increased somal size. In frontotemporal lobe dementia (FTLD) and Tauopathy model Tg4510, we see cytosis paired with macrophagicity (CD68 positive) in any kind of morphological state, while somal size is smaller and cells are not re-ramified at late stage. In amyotrophic lateral sclerosis (SOD1G93A), we found a 40-fold increase of large ramifying microglia with strong de-ramification. Last but not least, Rett syndrome mice with immune deficiency seem to lose the ability to change ramification and both small and large ramifying cells are significantly reduced. All those findings do not fit into the classical understanding of microglial reactivity as found in cell culture.


Methods: We developed a tool set for histological post mortem quantification of microglial morphology. This set includes classical Iba1 counting widened with type classification by computer learned algorithms and additional structural analysis of somal size, branching and process lengths. Together those data define a pattern of microglial reactivity.


Results: Finally we found out that we are able to distinguish the type of disease by pattern match of microglial alterations in Rett syndrome, AD, FTLD, Tauopathy and ALS models measured in controls of a series of preclinical studies.


Conclusions: Those data suggest to rethink the hitherto theory for ex vivo work and rather in first line to compare these patterns with those found in human disease samples and in second, to find out which mechanisms are responsible for the diversity of microglial reactivity patterns in different disease types.