The two faces of microglia

Formation of Alzheimer plaques by accumulation of b amyloid proteins are a hallmark of Alzheimer’s disease. Amyloid oligomers and plaques have been considered the primary cause of synaptotoxicity in patients suffering from the neurodegenerative disease that affects 44 million elderly people globally. To determine if and how the brain’s immune system contributes to amyloid clearance and thus preserves neurodegeneration, which is mediated by loss of synapses, Swiss, British, and US researchers, headed by Lawrence Rajendran from University Zurich, conducted loss-of-function experiments in glia cells, knocking out the most common 18 genes linked to neurodegenerative proteinopathies of the brain. As glia cells are known to remove cell debris, such as degenerated proteins, it seemed an attractive hypothesis that b amyloid depletion is driven by factors affecting the phagocytotic activity of the brain’s innate immune cells.

In a siRNA screen, post-doc researcher Rosa Chiara Paolicelli, in fact found that genes affecting neurodegeneration sped up b amyloid phagocytosis when silenced in mice. The most pronounced effect was seen with TDP-43, a transcriptional repressor (Neuron, doi: 10.1016/j.neuron.2017.05.037). To her surprise, she made an additional observation. Despite the reduction in amyloid load, she found a significant decrease in synaptic markers in these mice. This points to re-activation of a glia cell function. So far this was only observed in post-natal brain development, during which the brain is rewired including degradation of synapses, the connection between neurons, which is crucial for proper cognitive function. Quantification of the synaptic marker vGlut1 confirmed a drastic reduction in glutamatergic synapses, suggesting that abnormally phagocytic microglia remove not only amyloid but also synapses. Futher experiments showed that TDP-43-mediated synapse degradation occured regardless of the presence of amyloid.  

New paradigm of neurodegeneration?

cytosis and clearance elicited in microglia following TDP-43 loss is ultimately paradoxical,” the researchers conclude. “These processes are not entirely beneficial in the context of a complex organism, since microglial phagocytic activity might not only enable clearance of protein aggregates but also synaptic connection loss.” According to Rajendran, “These mixed responses may underlie the failure of many AD drug treatment clinical trials to improve cognitive function, despite the progressive reductions in amyloid burden.”

Up to now, it is not known which factors drive TDP-43-driven synaptic degradation. ”Nutrient depletion in the ageing brain might boost phagocytotic activity of the microglia, thus triggering synaptic loss,” speculates Rajendran. Though identification of such metabolic trigger factors seen far off, the new mechanism of TDP-43-mediated neurotoxicity could  trigger causative approaches to treat neurodegeneration.

 (First published in European Biotechnology, Autumn Edition 2017)