Related Experiment Videos
Plaque-dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse
Monika Plescher1,2,3, Gerald Seifert3, Jan Niklas Hansen1,2
1German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany.
Abstract:
Microglia, the central nervous system resident innate immune cells, cluster around Aβ plaques in Alzheimer's disease (AD). The activation phenotype of these plaque-associated microglial cells, and their differences to microglia distant to Aβ plaques, are incompletely understood. We used novel three-dimensional cell analysis software to comprehensively analyze the morphological properties of microglia in the TgCRND8 mouse model of AD in spatial relation to Aβ plaques. We found strong morphological changes exclusively in plaque-associated microglia, whereas plaque-distant microglia showed only minor changes. In addition, patch-clamp recordings of microglia in acute cerebral slices of TgCRND8 mice revealed increased K+ currents in plaque-associated but not plaque-distant microglia. Within the subgroup of plaque-associated microglia, two different current profiles were detected. One subset of cells displayed only increased inward currents, while a second subset showed both increased inward and outward currents, implicating that the plaque microenvironment differentially impacts microglial ion channel expression. Using pharmacological channel blockers, multiplex single-cell PCR analysis and RNA fluorescence in situ hybridization, we identified Kir and Kv channel types contributing to the in- and outward K+ conductance in plaque-associated microglia. In summary, we have identified a previously unrecognized level of morphological and electrophysiological heterogeneity of microglia in relation to amyloid plaques, suggesting that microglia may display multiple activation states in AD.
Insights
Microglia near amyloid plaques in Alzheimer's disease show distinct morphological and electrical changes, indicating varied activation states. These plaque-associated microglia exhibit unique ion channel activity not seen in distant cells.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are immune cells in the brain that respond to Alzheimer's disease (AD) pathology.
- Their specific activation states around amyloid-beta (Aβ) plaques are not fully understood.
Purpose of the Study:
- To investigate the morphological and electrophysiological differences between microglia associated with Aβ plaques and those distant from them in an AD mouse model.
- To identify the ion channels responsible for altered microglial function near plaques.
Main Methods:
- Utilized novel 3D cell analysis software to examine microglial morphology in relation to Aβ plaques in TgCRND8 mice.
- Performed patch-clamp recordings on microglia in acute brain slices.
- Employed pharmacological channel blockers, multiplex single-cell PCR, and RNA fluorescence in situ hybridization.
Main Results:
- Plaque-associated microglia displayed significant morphological alterations, unlike plaque-distant microglia.
- Increased potassium (K+) currents were observed in plaque-associated microglia, with two distinct electrophysiological profiles identified.
- Kir and Kv ion channels were implicated in the altered K+ conductance of plaque-associated microglia.
Conclusions:
- Microglia exhibit significant morphological and electrophysiological heterogeneity in response to Aβ plaques in AD.
- The plaque microenvironment differentially influences microglial ion channel expression, suggesting multiple activation states.
- These findings provide new insights into microglial responses in Alzheimer's disease.