Destruction of Brain Cell Connections May Be The Earliest Indicator Of Alzheimer’s

Alzheimer's disease may begin with a process known as synaptic protein. Fresnel/Shutterstock

The destruction – or “pruning” – of the connections between brain cells appears to occur at a much earlier stage in the development of Alzheimer’s disease than previously thought, and probably begins before other tell-tale signs of the disorder can be detected. A new study in the journal Science outlines the chain of events that causes this phenomenon, potentially providing researchers with a new focus in their efforts to treat the condition.

Among Alzheimer’s disease’s biggest giveaways is the presence of plaques made of proteins called amyloid-beta proteins on the brains of sufferers. These plaques are known to damage neurons and accelerate cognitive decline. However, some studies have shown that the loss of connections between neurons – known as synapses – can begin before these plaques start to appear, and may therefore represent an earlier marker of the disorder.

The loss of synapses is known as synaptic pruning, and is caused by immune cells called microglial cells, which engulf these synapses in the same way that white blood cells do to invading pathogens. This process plays an important role in shaping the young brain, but tends to cease later in life once the brain is fully developed.

Bearing this in mind, the study authors suspected that “microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in Alzheimer’s disease.” To test this, they used a technique called super-resolution structured illumination microscopy to measure the synaptic density in the brains of mice that had been genetically engineered to develop Alzheimer’s.

In doing so, they discovered that synapses did indeed begin to disappear before the development of amyloid-beta plaques. This led the researchers to question whether the initial appearance of soluble amyloid-beta proteins – before they have had time to form into solid clumps – provides the spark for this early synaptic pruning.

Neurons connect at junctions called synapses, although the destruction of these connections can lead to cognitive decline. nobeastsofierce/Shutterstock

To investigate this, they injected these mice with a chemical that reduced the concentration of soluble amyloid-beta proteins in their brain, before testing for levels of a compound called C1q. This compound plays a key role in synaptic pruning by recruiting a protein called C3 to bind to synapses, labeling them for destruction by microglia.

Results showed a marked decrease in C1q levels when soluble amyloid-beta was removed, indicating that these proteins may be responsible for stimulating synaptic pruning in Alzheimer’s. To confirm this, the researchers injected soluble amyloid-beta proteins into mice that had been genetically engineered to lack C1q, and found that no synaptic loss occurred.

Summarizing their findings, the study authors claim that “microglia in the adult brain, when challenged with synaptotoxic, soluble amyloid-beta oligomers, engulf synapses in the absence of plaque aggregates.” Knowing this could prove invaluable to those developing new treatments for Alzheimer’s by allowing them to detect the condition at an earlier stage and target the interruption of synaptic pruning.

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