How the brain's 'memory replay' goes wrong in Alzheimer's disease

(Press-News.org) Memory dysfunction in Alzheimer’s disease may be linked to impairment in how the brain replays our recent experiences while we are resting, according to a new study in mice by University College London (UCL) scientists.

The researchers say their findings, published in Current Biology, could help scientists develop drug treatments targeting this impaired brain function, or help design new tests for early diagnosis.

Co-lead author Dr Sarah Shipley (UCL Cell & Developmental Biology) said: "Alzheimer's disease is caused by the build-up of harmful proteins and plaques in the brain, leading to symptoms such as memory loss and impaired navigation — but it's not well understood exactly how these plaques disrupt normal brain processes.

"We wanted to understand how the function of brain cells changes as the disease develops, to identify what's driving these symptoms.

“When we rest, our brains normally replay recent experiences — this is thought to be key to how memories are formed and maintained. We found this replay process is disrupted in mice engineered to develop the amyloid plaques characteristic of Alzheimer's, and this disruption is associated with how badly animals perform on memory tasks."

The replay process, which occurs in the brain’s hippocampus, involves place cells firing in rapid sequences during rest. Place cells — discovered by Nobel prize-winning UCL neuroscientist Professor John O'Keefe — are neurons (brain cells) that represent specific locations. When we visit somewhere, particular place cells fire, and as we move the cells fire in a sequence. Later, when we rest, these cells reactivate in the same sequence, helping memories become ingrained.

For the study, the researchers were testing how well mice performed in a simple maze task, while monitoring their brain activity with sets of electrodes that could simultaneously track roughly 100 individual place cells.

In mice with amyloid pathology, the replay process was fundamentally altered. Surprisingly, replay events occurred just as frequently as in healthy mice — but their structure was disorganised. The normal, coordinated patterns of place cell activity that should reinforce memories were scrambled. The researchers also found that place cells in affected mice became less stable over time, with individual neurons no longer reliably coding the same locations, particularly after rest periods — precisely when replay should be strengthening these representations.

This disruption had consequences on memory tasks: affected mice performed worse in the maze, appearing to forget where they had already been and revisiting corridors that led nowhere.

Co-lead author Professor Caswell Barry (UCL Cell & Developmental Biology) said: "We've uncovered a breakdown in how the brain consolidates memories, visible at the level of individual neurons. What's striking is that replay events still occur — but they've lost their normal structure. It's not that the brain stops trying to consolidate memories; the process itself has gone wrong.

"We hope our findings could help develop tests to detect Alzheimer's early, before extensive damage has occurred, or lead to new treatments targeting this replay process. We're now investigating whether we can manipulate replay through the neurotransmitter acetylcholine, which is already targeted by drugs used to treat Alzheimer's symptoms. By understanding the mechanism better, we hope to make such treatments more effective."

The research was conducted by researchers in the UCL Faculties of Life Sciences and Brain Sciences, and supported by the Cambridge Trust, Wellcome, and the Masonic Charitable Foundation.

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