The case of the missing neurons

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An amyloid plaque in the brain

Alzheimer’s disease is characterised by the substantial loss of neurons (nerve cells) in the brain. However, when researchers examine the brains of people who have died with Alzheimer’s, they do not see more dead neurons than in people of the same age without Alzheimer’s. Thousands of cells missing, presumed dead, but how can we solve the mystery – and stop it happening in others – if there are no bodies?

To discover what’s going on, we have to consider what might be killing the neurons and how. Another characteristic of Alzheimer’s is the presence of ‘plaques’ of a substance called amyloid beta that accumulate in between brain cells. In the laboratory, a high concentration of amyloid beta will kill neurons directly, but it is likely that much lower concentrations of amyloid beta occur in Alzheimer’s patients’ brains in real life.

In this case, it seems that amyloid beta can recruit an unwitting accomplice to do the dirty work: microglial cells, part of the brain’s local immune system. Researchers studying how microglial cells kill their prey – which under healthier circumstances might be viruses or bacteria – have recently discovered a new modus operandi. As well as using weapons like oxidants, nitric oxide, glutamate or proteases to kill unwanted invaders, microglial cells can also swallow their prey whole using a well-known process called phagocytosis.

However, whereas standard phagocytosis is deployed to clear the bodies after the victim has died, microglial cells can also eat their prey alive. This would certainly account for the lack of dead neurons at the scene of the crime in Alzheimer’s disease.

PS: “Eat me”

In a paper published last November in the Journal of Biological Chemistry, Wellcome Trust-funded researchers at the University of Cambridge detail painstaking detective work finding out whether this is indeed the answer to the puzzle. The case they build is convincing.

Microglial cells do not just go around eating everything all the time. They need to be activated and even then they will only eat cells that are labelled with a molecule called phosphatidylserine (PS). It turns out that amyloid beta can arrange both conditions: it activates phagocytosis by microglial cells and persuades neurons to express PS – the “eat me” signal – on their surface membranes. Then, the amyloid beta can sit back and let the microglial cells consume the neurons, killing them and disposing of the evidence in one fell swoop.

Twists and tangles

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A case for Hercule Poirot, perhaps: "What has happened to those little grey cells, Hastings?"

Don’t close that case file just yet, though. As the researchers note in their paper, it will be challenging to verify that this process is what’s actually killing neurons in the brains of Alzheimer’s patients: “Primary phagocytosis (unlike apoptosis or necrosis [the two most common mechanisms of cell death]) leaves no cell corpse to diagnose the cause of death.”

Nevertheless, their research so far is a compelling explanation of the missing neuron bodies and suggests that blocking microglial phagocytosis, or preventing the “eat me” signal being read, could be used as a treatment for Alzheimer’s.

But in one final twist, the researchers also tentatively suggest that amyloid beta may, in this scenario, play a beneficial role in the healthy brain. Its ability to activate primary phagocytosis of neurons may be useful when the brain wants to rewire itself – so-called ‘synaptic plasticity’, which is when neurons make new connections between each other, and is essential for learning, development and memory.

This perhaps explains what amyloid beta is doing in our brains in the first place, and why it should cause disease when it malfunctions. But it may also mean we have to be very careful if we target it in an attempt to treat people with Alzheimer’s disease.

The case continues….

Reference:

Neniskyte U, Neher JJ, & Brown GC (2011). Neuronal death induced by nanomolar amyloid β is mediated by primary phagocytosis of neurons by microglia. The Journal of biological chemistry, 286 (46), 39904-13 PMID: 21903584

Image credits: Med. Mic. Sciences, Cardiff Uni / Wellcome Images (amyloid plaque); MRC Toxicology Unit / Wellcome Images (phagocytosis video); elena-lu on Flickr (screenshot from ITV’s ‘Poirot’)

Image may be NSFW.
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Image may be NSFW.
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