Alzheimer’s Disrupts Brain’s Memory Replay During Rest

Scientists at University College London have discovered that in mice with conditions mimicking Alzheimer's disease, the brain's process of replaying recent experiences during rest periods becomes scrambled. This disruption prevents memories from forming properly, causing the animals to forget paths they have taken. The work points to a key failure in how the brain handles memory when idle.

Background

The brain does not stop working when a person or animal rests. Instead, it reviews what happened earlier in the day. This replay helps lock in memories, especially those about places and paths. It happens in a part of the brain called the hippocampus, which handles learning and recall.

Certain brain cells, known as place cells, play a main role here. These cells fire when someone moves through a space, each one linked to a specific spot. As the body travels, the cells light up in a set order. Later, during rest, they fire again in the same order but much faster. This quick replay strengthens the memory of that path.

Professor John O'Keefe, a Nobel Prize winner at University College London, first identified these place cells years ago. His work showed how they build mental maps of surroundings. In healthy brains, rest replays keep these maps sharp and reliable.

Alzheimer's disease changes this picture. It involves buildups of proteins called amyloid plaques in the brain. These plaques harm cells and lead to memory loss. People with Alzheimer's often forget recent events or familiar places. Researchers have long wondered why this happens at the cell level.

To explore this, the University College London team used mice bred to develop amyloid plaques, much like humans with early Alzheimer's. They watched brain activity as the mice ran mazes and then rested. The goal was to see if replay still worked or if the plaques broke it.

Key Details

The study tracked about 100 place cells at once using fine electrodes placed in the hippocampus. Healthy mice showed clear patterns. After running a maze, their place cells replayed the path in order during rest. These replays happened often and stayed structured over time.

In the Alzheimer's-like mice, replays still took place at the same rate. But the patterns fell apart. The sequences no longer matched the real paths taken. Cells that should fire together did not coordinate well. Over sessions, individual place cells lost their link to specific spots. They became unstable, firing for different locations each time.

This instability grew worse after rest periods. Normally, rest should firm up these links, but in affected mice, it made them weaker. The researchers noted that the more scrambled the replays, the less stable the cells became.

Behavioral Tests in the Maze

The team tested memory with a radial arm maze. This setup has several arms leading to rewards. Healthy mice learned quickly which arms they had visited and avoided repeats. They remembered paths well.

Affected mice struggled. They went back to arms they had already checked, even after many tries. This showed they could not hold onto location memories. The poor maze performance matched the scrambled replays and unstable cells seen in the brain data.

Co-lead author Professor Caswell Barry explained the core issue:

"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."

Professor Barry, from University College London's Cell and Developmental Biology department, pointed out that the brain keeps attempting the replay. The problem lies in the poor organization.

Another team member, Sarah Shipley, a senior research fellow in the same department, added detail on the observations:

"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 mice came from a specific line called App NL-G-F knock-in. This model builds amyloid plaques without changing other genes much, making it a good stand-in for human disease.

What This Means

These findings show memory loss in Alzheimer's starts with a specific breakdown. The hippocampus tries to replay experiences but cannot do it right because of amyloid plaques. Place cells lose their steady role in mapping spaces. Over time, this erodes the ability to remember where one has been or gone.

The work suggests ways to spot Alzheimer's early. Doctors might one day measure replay patterns during rest to catch changes before bigger damage sets in. Brain scans or simple tests could check place cell stability.

Treatment ideas flow from this too. The team plans to test ways to fix replay. One focus is acetylcholine, a brain chemical already targeted by some Alzheimer's drugs. These medicines ease symptoms but do not stop the disease. Better understanding of replay might improve them.

Professor Barry noted future steps:

"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."

This could mean drugs that restore order to replays, helping cells stay stable. Other approaches might boost rest-time activity in the hippocampus.

The study adds to knowledge of how Alzheimer's hits memory first. It affects daily tasks like finding one's way home or recalling a recent talk. For the millions living with the disease, even small fixes to replay could mean better recall and more independence.

Researchers stress that while done in mice, the hippocampus and place cells work much the same in humans. Human studies could build on this, perhaps using implants or scans to watch replays in patients.

The paper appeared in Current Biology. It builds on years of work linking rest, replay, and memory. Past studies showed replay aids learning, but this is the first clear look at its failure in an Alzheimer's model.