A faulty protein called beta-amyloid clumps together and destroys the microscopic connections between brain cells that are essential for memory, and a new imaging technique is now revealing exactly how this damage happens at the molecular level. This matters because Alzheimer’s disease affects more than 47 million people worldwide, a number projected to exceed 130 million by 2050, and currently no treatment can prevent or slow its progression. The loss of synapses—the brain’s microprocessors for encoding memories—is a direct contributor to the memory loss that defines the disease, yet the precise mechanism by which amyloid pathology damages these connections remains unknown. The researcher is using cryo-electron tomography to visualise faulty proteins in unprecedented detail within intact brain samples, including postmortem tissue donated by Alzheimer’s patients. This is fundamental science: it aims to reveal the molecular and cellular processes unfolding around amyloid clumps in real tissue, not to test a drug or therapy. If successful, the work could identify novel drug targets for intervention, potentially leading to a mechanism-based therapy that slows or halts synapse destruction—a step that would reduce the £26 billion annual cost of dementia in the UK and ease the burden on millions of families.
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More than 47 million people live with dementia worldwide, of which Alzheimer's disease is the most common form. This number is projected to increase to more than 130 million by 2050. Because Alzheimer's disease progresses over many years, it also imposes a large economic and societal burden, including £26 billion cost a year in the UK. Currently, no treatments are available to prevent or slow the progression of this disease. The first clinical indicator of Alzheimer's dementia is the loss of memory. Connections between the nerve cells in the brain, called synapses, are the microprocessors of the mind that are essential for us to be able to encode and store memories. In Alzheimer's disease, synapses are damaged or destroyed by a faulty protein called beta-amyloid that clump together and accumulate in the brain. The loss of synapses contributes to memory loss in people with Alzheimer's disease. My research is aimed at understanding how synapses are damaged by Alzheimer's disease and how this is linked to the accumulation of amyloid. This is achieved by using recent developments in a method called cryo-electron microscopy, which enables us to see the faulty proteins in very high levels of detail and to find out how they damage synapses. In addition, we have developed workflows that allow us to apply these imaging techniques on intact brain samples to better understand the underlying molecular and cellular processes that are ongoing in and around the amyloid pathology that defines this disease. Importantly, we are in a position to apply this approach to postmortem brain samples donated by Alzheimer's patients who have succumbed to the disease. The insights obtained from this research are expected to reveal novel drug targets for intervention that could in the long-term contribute to the development of a mechanism-based therapy.
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