Loss of TDP-43 Points to Microglia as a Cause of Lost Synapses in Alzheimer’s Disease

The protein TDP-43 acts as a regulator of autophagy, among other things: more of it means less autophagy. The presence of increased amounts of TDP-43 has been investigated in the context of ALS and frontotemporal dementia, where it appears to cause more dysfunction than would be expected just from a loss of the cellular maintenance processes of autophagy. In this recent research, the focus is instead on Alzheimer’s disease, where researchers discovered that reducing TDP-43 levels makes the immune cells called microglia more efficiently clear out the β-amyloid associated with this condition. Unfortunately, microglia are also involved in generation and maintenance of synapses, and loss of TDP-43 turns out to ensure that synapses are removed as well as the amyloid. Overall it seems that the amount of TDP-43 in circulation has a narrow safe range; therapies targeting it would have to be more sophisticated than just a blanket reduction or increase via pharmaceuticals. On the plus side, this research adds to the evidence for changes in microglia behavior to be important in neurodegenerative diseases, and there are many other options when it comes to adjusting the activities of these cells.

For the first time, researchers demonstrate a surprising effect of microglia, the scavenger cells of the brain: If these cells lack the TDP-43 protein, they not only remove Alzheimer’s plaques, but also synapses. This removal of synapses by these cells presumably leads to neurodegeneration observed in Alzheimer’s and other neurodegenerative diseases. Alzheimer’s is a disease in which the cognitive abilities of afflicted persons continuously worsen. The reason is the increasing loss of synapses, the contact points of the neurons, in the brain. In the case of Alzheimer’s, certain protein fragments, the β-amyloid peptides, are suspected of causing the death of neurons. These protein fragments clump together and form the disease’s characteristic plaques.

In an initial step, the researchers looked at the effect that certain risk genes for Alzheimer’s have on the production of the β-amyloid peptide. They found no effect in neurons. This led the researchers then to examine the function of these risk genes in microglia cells – and made a discovery: If they turned off the gene for the TDP-43 protein in these scavenger cells, these cells remove β-amyloid very efficiently. This is due to the fact that the lack of TDP-43 protein in microglia led to an increased scavenging activity, called phagocytosis.

In the next step, researchers used mice, which acted as a disease model for Alzheimer’s. In this case, as well, they switched off TDP-43 in microglia and observed once more that the cells efficiently eliminated the β-amyloid. Surprisingly, the increased scavenging activity of microglia in mice led also to a significant loss of synapses at the same time. This synapse loss occurred even in mice that do not produce human amyloid. This finding that increased phagocytosis of microglia can induce synapse loss led researchers to hypothesize that perhaps, during aging, dysfunctional microglia could display aberrant phagocytic activity. The results show that the role of microglia cells in neurodegenerative diseases like Alzheimer’s has been underestimated. It is not limited to influencing the course of the disease through inflammatory reactions and the release of neurotoxic molecules as previously assumed. Instead, this study shows that they can actively induce neurodegeneration.

Link: http://bit.ly/2t856ON

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