For the first time, researchers at the University of Zurich have demonstrated 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 lead to neurodegeneration observed in Alzheimer's and other neurodegenerative diseases.
Similar to other neurodegenerative disorders, 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.
Voracious microglia cells destroy brain synapses
Together with researchers from Great Britain and the United States, the group of Lawrence Rajendran from the Institute for Regenerative Medicine of the University of Zurich now shows that dysfunctional microglia cells contribute to the loss of synapses in Alzheimer's and other neurodegenerative diseases. These scavenger cells usually monitor the function of neurons in the brain by removing excess synapses during development or toxic protein aggregates. Until now, their role in neurodegenerative disorders remains controversial.
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.
The TDP-43 protein regulates the activity of scavenger cells
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. “Nutrient deprivation or starvation-like mechanism during aging could enhance phagocytic mechanism in microglia and this could lead to synaptic loss" Lawrence Rajendran assumes.
Direct role in neurodegeneration
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. "Dysfunction of the microglia cells may be an important reason why many Alzheimer's medications reduce the amyloid plaques in clinical testing, but the cognitive functions in patients do not lead to improvement," Rajendran says.
This work was supported by the Swiss National Science Foundation, Velux Foundation, Synapsis Foundation, Cure Alzheimer Fund and the Forschungskredit of the University of Zurich.
Rosa C. Paolicelli, Ali Jawaid, Christopher M. Henstridge, Andrea Valeri, Mario Merlini, John L. Robinson, Edward B. Lee, Jamie Rose, Stanley Appel, Virginia M.-Y. Lee, John Q. Trojanowski, Tara Spires-Jones, Paul E. Schulz, and Lawrence Rajendran. TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron. 29 June 2017; doi:1016/j.neuron.2017.05.037
Prof. Lawrence Rajendran, PhD
Institute for Regenerative Medicine
University of Zurich
Phone: +41 44 634 88 60
Kurt Bodenmüller | Universität Zürich
Progress in Super-Resolution Microscopy
17.12.2018 | Julius-Maximilians-Universität Würzburg
Communication between neural networks
17.12.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.
Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...
The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.
Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...
What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
17.12.2018 | Studies and Analyses
17.12.2018 | Life Sciences
17.12.2018 | Power and Electrical Engineering