Alzheimer’s disease, a form of dementia, accounts for 60-80% of cases in the UK.
Researchers have long linked Alzheimer’s to a buildup of amyloid plaques and tau tangles in the brain. These are both proteins that have been compared to the “trigger and bullet” in the development of the condition.
But we don’t have a single cause of the disease. Nor do we know what kicks off the problematic buildup of amyloid plaques and tau tangles, which seems to begin years before symptoms appear.
However, a new paper published in Nature has suggested that a molecular “switch” called ERBB4 may set up a chain reaction when activated in the wrong neurons, which could lead to cognitive impairment.
What did the study find?
The researchers initially began by looking at astrocytes and microglia in mice. These are types of cells called glial cells that protect and maintain brain health.
Healthy glial cells can remove “waste” synapses, or points of contact between communicating neurons, from the brain. The scientists wondered whether they become overactive among those with dementia, removing necessary synapses (dementia is linked to disappearing synapses).
But using mouse models of Alzheimer’s disease, they found this wasn’t straightforward.
Among mice with dementia, glial cells removed less of one kind of synapse (inhibitory synapses, which can inhibit neuron activity) and selectively engulfed more excitatory synapses (which tend to lead to more neuron activity).
So, researchers tried to change the neurons themselves to see if they had any influence on this pattern.
They found that glial activity increased and decreased according to signals from neurons. This seemed to apply to problematic changes, like selective over- and under-activity.
The unusual behaviour of glial cells may be linked to dementia development.
Certain early excitatory neurons seemed to contain errant ERBB4 among mice with dementia
Early in the mice’s Alzheimer’s disease, researchers noticed that a distinct population of excitatory neurons that had unexpectedly activated ERBB4 appeared.
ERBB4 is a receptor that helps cells to transmit signals. In healthy brains, it’s usually found in the inhibitory neurons – which can act as a kind of brake.
But mice with Alzheimer’s disease seemed to have active ERBB4 in excitatory neurons (these could be compared to an accelerator).
Not only that, but when the scientists used gene editing to remove ERBB4 from the excitatory neurons of Alzheimer’s model mice, the change made their nerve cells less reactive and seemed to correct unusual brain behaviour.
Mice also did better on memory and spatial cognition tests. These benefits lasted, too.
Meanwhile, when scientists activated ERBB4 in some of the mice’s excitatory neurons, they seemed to develop cognitive impairment, and some of their brain circuits became overactive.
Additionally, post-mortem tissue from the brains of hundreds people found that ERBB4 expression was elevated in excitatory neurons among those with Alzheimer’s disease.
The paper concluded, “These findings identify aberrant ERBB4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases”.
