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Mysterious shrunken cells have been spotted in the human brain for the first time, and appear to be associated with Alzheimer’s disease.

“We don’t know yet if they’re a cause or consequence,” says of Laval University in Québec, Canada, who presented her discovery at the conference in Big Sky, Montana, last week.

The cells appear to be withered forms of microglia – the cells that keep the brain tidy and free of infection, normally by pruning unwanted brain connections or destroying abnormal and infected brain cells.

But the cells discovered by Tremblay appear much darker when viewed using an electron microscope, and they seem to be more destructive. “It took a long time for us to identify them,” says Tremblay, who adds that these shrunken microglia do not show up with the same staining chemicals that normally make microglia visible under the microscope.

Smothering connections

Compared with normal microglia, the dark cells appear to wrap much more tightly around neurons and the connections between them, called synapses. “It seems they’re hyperactive at synapses,” says Tremblay. Where these microglia are present, synapses often seem shrunken and in the process of being degraded.

Tremblay in mice, finding that they increase in number as mice age, and appear to be linked to a number of things, including stress, the neurodegenerative condition Huntington’s disease and a mouse model of Alzheimer’s disease. “There were 10 times as many dark microglia in Alzheimer’s mice as in control mice,” says Tremblay.

Now she has detected these cells in people for the first time. Examining the brain of a person with Alzheimer’s disease who died at the age of 45, she found around twice as many dark microglia as in a brain from a healthy person of the same age.

“Understanding the identity and function of these dark microglia is an important question,” says of Trinity College Dublin, Ireland, who studies microglia. “It could be that dark microglia contribute to harmful processes during dementia,” he says.

Stress damage

Why these microglia seem to be smothering brain connections is unclear. It may be due to erroneous signalling, or the microglia may have gone into overdrive in an effort to protect the brain, says Tremblay.

Alternatively, the cells may have been damaged. The dark microglia seem to have shrunk in response to suffering a form of stress – exposure to reactive forms of oxygen that damage cells. As the cells get smaller, they appear darker under the microscope – a phenomenon also seen in stressed neurons. Further experiments revealed that these dark microglia have damaged proteins, DNA and other cell components. “That probably has an effect on their behaviour,” says Tremblay.

It’s possible that these microglia turn dark after experiencing stress that is associated with inflammation elsewhere in the body. “Studies in patients show that inflammation arising outside the brain is associated with more rapid decline in Alzheimer’s patients, and it’s important to unravel what role microglia might play in this acceleration of disease,” says Cunningham.

But we do not yet know if these dark microglia make any difference to health at all, says at Stanford University. “In disease, microglia are known to exist in different states,” he says. “The question is, do they alter microglia behaviour and cause Alzheimer’s?”

Read more: The mind minders: Meet our brain’s maintenance workers