Scientists from the Universities of Zurich, Pennsylvania and Edinburgh have used animal models to look into the biology of neurodegenerative diseases. A type of brain cell called microglia has so far been considered to be protective, as it clears up toxic amyloid plaques in the brain that lead to the development of Alzheimer’s dementia. However, the authors found that if microglia lack a certain protein (TDP-43), it not only removes amyloid plaques but also connections between nerve cells called synapses.
We know from existing research that increased levels of toxic amyloid protein in the brain is a major hallmark of Alzheimer’s disease pathology. The authors of the new study initially set out to investigate how certain risk genes for Alzheimer’s disease affected the production of toxic amyloid – but found that none of the risk genes they looked at had any effect on the production of amyloid in the major cells of the brain called neurons. Using animal models the international group of scientists then looked into the role of microglia – a cell that’s role is to clear up toxins in the brain. They found that removing a gene called TDP-43 only from microglial cells, led to the microglia becoming overactive. The process of toxin and debris clearance in microglia is called phagocytosis and this process was hyperactive in the TDP-43 depleted microglia. Importantly, these overactive microglia not only cleared away amyloid (when present) they also turned against the brain’s synapses and destroyed them. Interestingly, the authors found that overt phagocytosis occurred even if there was no amyloid to clear up, suggesting that these TDP-43 depleted cells attacked synapses. . This is an important finding, as TDP-43 is a protein mainly associated with Frontotemporal Lobe Dementia (FTLD) and Motor Neurone Disease (MND) – both of these diseases are characterised by a loss of synapses.
Dr Chris Henstridge (pictured) and Dr Tara Spires-Jones from the Basic science domain of the Centre for Dementia Prevention are co-authors of the paper. Dr Henstridge described the findings as important for a number of reasons. He said “Firstly, it provides new evidence that cells within the brain might be attacking others, leading to neurodegeneration. Secondly, it identifies rogue microglia as a potential source of specific synapse loss in the brain of Alzheimer’s and MND patients. Thirdly, it unveils microglial cells as a potential therapeutic target that could be exploited pharmaceutically. This is very important given the current lack of effective medications available for Alzheimer’s disease and MND.”
Paolicelli, R.C., Jawaid, A., Henstridge, C.M., Valeri, A., Merlini, M., Robinson, J.L., Lee, E.B., Rose, J., Appel, S., Lee, V. M.-Y. , Trojanowski, J.Q., Spires-Jones, T., Schulz, P.E., Rajendran, L. (2017). TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron