Microglial cells in the brain play an important but paradoxical role in neurodegenerative diseases. When highly active, they proliferate and take on an amoeboid form (in contrast to their normally branched structure). Specific protein complexes, so-called inflammosomes, are then formed within the cells. They are part of the innate immune response and respond quickly to foreign proteins and inflammatory signals.
This process requires an adapter protein to bind caspase, which produces inflammatory molecules such as IL-1β and TNFα from their precursors. The release of these cytokines then activates defined signalling pathways via special receptors in nerve cells, including the p38 MAP kinase pathway, which causes phosphorylation of tau proteins and thus neuronal damage. In mouse models of Alzheimer's disease, activated microglia facilitates the clearance of β-amyloid (Aβ) accumulations in the brain, but unfortunately is also involved in the unwanted degradation of synapses, which accelerates neurodegeneration and cognitive deficits.
Zezhong Lv and colleagues from Yang Zhan's research group in Shenzhen (China) have now discovered the complement protein C1q, which is responsible for the targeted removal of synapses, but apparently not for the reduction of amyloid plaques. This is the first time scientists have been able to demonstrate a therapeutic approach that utilises the positive aspects of microglia activation while at the same time preventing its harmful effects on neurons.
For their experiments, the authors of the paper recently published in Neuron used a modern optogenetic technique to activate microglia with blue light. Such methods serve as precision instruments for activating cells without damaging them. The excitation of so-called channelrhodopsins leads to a depolarisation of the plasma membranes via ions entering the cell. Although microglial cells are not actually excitable, their activity can be influenced by electrical stimulation and optogenetic methods because they normally maintain a hyperpolarised membrane potential that is mediated by THIK1 channels. Inhibition of these channels depolarises microglial cells, activates them and increases their phagocytotic activity.
In mice infused with β-amyloid, but also in genetically modified Alzheimer's mice, the optogenetic stimulation of microglia in the hippocampus now led to the degradation of Aβ and the reduction of synapses and dendritic processes (spines). Detailed examination of the brain tissue revealed increased markers for phagolysosomes, enhanced levels of the complement factor C1q, but also a reduction in synapses in the stimulated area (microglia is the most important producer of C1q in the central nervous system).
Interestingly, blocking C1q with antibodies prevented the loss of synapses induced by optogenetics without affecting microglial activation or Aβ uptake. Should the increase in C1q be observed in early-stage Alzheimer's disease patients in a similar manner as in animal models, these findings could pave the way for the use of microglia to clear toxic Aβ deposits but preserve synapses and thus neuronal connections via C1q blockade.
Reference:
Lv Z, Chen L, Chen P, Peng H, Rong Y, Hong W, Zhou Q, Li N, Li B, Paolicelli RC, Zhan Y (2024) Clearance of β-amyloid and synapses by the optogenetic depolarisation of microglia is complement selective. Neuron 112:740
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