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Lost connections in the brains of mice with Alzheimer’s restored by MRC LMB in Cambridge




An artificial molecule has been created that was able to restore lost connections in the brain and spinal cord of mice with neurological disorders, improving their memory, co-ordination and movement.

The astonishing work by scientists at the MRC Laboratory of Molecular Biology (LMB) in Cambridge and their international collaborators offers long-term hope of helping patients with a range of conditions including Alzheimer’s disease, spinal injury and epilepsy.

Radu Aricescu in the MRC Laboratory of Molecular Biology's Neurobiology Division. Picture: MRC LMB
Radu Aricescu in the MRC Laboratory of Molecular Biology's Neurobiology Division. Picture: MRC LMB

The researchers created a synthetic ‘molecular bridge’ to repair the neuronal circuits in mice with disease or injury.

Radu Aricescu, a group leader in the MRC LMB’s Neurobiology Division, said: “Damage in the brain or spinal cord often involves loss of neuronal connections in the first instance, which eventually leads to the death of neuronal cells.

“Prior to neuronal death, there is a window of opportunity when this process could be reversed in principle.

“We created a molecule that we believed would help repair or replace neuronal connections in a simple and efficient way.

“We were very much encouraged by how well it worked in cells and we started to look at mouse models of disease or injury where we see a loss of synapses and neuronal degeneration.”

Inside the human brain is a vast network of neurons, or nerve cells, that communicate with one another via connections known as synapses.

Damage in the brain or spinal cord often involves loss of these connections – a problem seen in many neuropsychiatric and neurological disorders.

Our synapses are built and remodelled throughout our life under the control of an array of different synaptic organiser proteins. These have a range of specific functions and are activein different regions of the brain.

Some of them directly connect proteins within the membranes of neurons to form molecular bridges that span synapses.

Radu’s group worked with researchers in Japan and Germany to design artificial molecules that reversed the loss of synapses.

Jonathan Elegheert and Amber Clayton, in Radu’s group, solved a series of synaptic organiser structures.

And Radu combined structural elements from two organiser proteins – known as organiser proteins cerebellin-1 and neuronal pentraxin-1 – to create the first synthetic synaptic organiser, called CPTX.

An illustration of how CPTX works by forming a molecular bridge between pre- and post-synaptic neurons. Graphic: MRC Laboratory of Molecular Biology
An illustration of how CPTX works by forming a molecular bridge between pre- and post-synaptic neurons. Graphic: MRC Laboratory of Molecular Biology

This created a bridge – between presynaptic neurexin and postsynaptic AMPA receptors – and induced the formation of ‘excitatory synapses’, which are the kind of connection that increases the firing action potential of a cell.

After successful experiments in cell cultures, researchers at Keio University and Aichi Medical University in Japan and DZNE Magdeburg in Germany tested the molecule on mice with cerebellar ataxia – damage in the brain that can result from many diseases. Patients with it can have problems with balance, gait and eye movements.

But when the molecule was injected into the brains of these mice, the team observed reconnection of synapses and restored motor co-ordination.

Further experiments also showed the molecule led to better performance in memory tests in mouse models of Alzheimer’s disease.

And the greatest impact was seen in mice with spinal cord injury, which showed improved movement and co-ordination for at least seven or eight weeks following a single injection into the site of injury.

In the brain, the positive impact of the injections last about a week in the ataxia model. Work to develop new and more stable versions of CPTX is under way.

Much more work is needed to discover if this could work in humans.

Summary of CPTX impact upon injection in animal models of Ataxia, Alzheimer’s Disease and spinal cord injury. Graphic: MRC Laboratory of Molecular Biology
Summary of CPTX impact upon injection in animal models of Ataxia, Alzheimer’s Disease and spinal cord injury. Graphic: MRC Laboratory of Molecular Biology

But the research could have numerous applications.

The LMB see it as a prototype of how structure-guided approaches can be used to repair neuronal circuits more generally, opening the way to many applications in neuronal repair and circuit engineering and remodelling.

And while CPTX was designed to restore lost connections that send excitatory signals, the same principle could be used to make inhibitory versions or to remove connections in disorders like epilepsy.

Radu added: “There are many unknowns as to how synaptic organisers work in the brain and spinal cord, so we were very pleased with the results we saw. We demonstrate that we can restore neural connections that send and receive messages, but the same principle could be used to remove connections. The work opens the way to many applications in neuronal repair and remodelling: it is only imagination that limits the potential for these tools.”

Kunimichi Suzuki, who worked on the research at Keio but is now based in Radu’s group at the LMB, is developing second generation synaptic organisers that will be tested in multiple animal models.

The findings were published in Science.

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