Place cells, hippocampal neurons discovered by Nobel laureate Dr. John O’Keefe, normally fire in vivid, rapid sequences at rest that recreate our recent experiences and aid in memory consolidation. But in Alzheimer’s disease, that internal rehearsal appears to be disabled. In a new study from University College London (UCL), researchers report that although hippocampal regeneration still occurs in mouse models of Alzheimer’s disease, its arrays have lost structure, suggesting a subtle but profound breakdown in the mechanisms that stabilize memory.
The works published in current biology And the title is “Impaired hippocampal regeneration is associated with reduced offline map stability in an Alzheimer’s disease mouse modelprovides a mechanistic glimpse into how memory begins to malfunction long before neurons die or areas of the brain visibly degenerate. This study suggests that the process is not missing, but rather dysfunctional. The brain tries to consolidate the memory, but the replay itself is scrambled.
“When we are resting, our brains typically replay recent experiences, and this is thought to be key to how memories are formed and maintained,” said co-first author Dr Sarah Shipley, a senior research fellow in UCL’s Department of Cell and Developmental Biology. “We found that this regenerative process was disrupted in mice engineered to develop amyloid plaques characteristic of Alzheimer’s disease, and that this disruption was associated with the animals’ poor performance on memory tasks.”
To investigate this breakdown, the research team focused on the hippocampus. In the hippocampus, place cells encode specific locations and fire in an ordered sequence as the animal moves through space. During breaks, the same sequences are reactivated in compressed bursts, replaying events that are thought to stabilize the spatial map and support long-term memory. The researchers monitored neural activity while the mice navigated a radial arm maze using an electrode array that could track about 100 place cells simultaneously.
In healthy mice, replay of resting events enhanced stable place cell representation. However, in the Alzheimer’s disease model (App NL‑G‑F knock-in line), the replay was fundamentally changed. The frequency of regeneration events remained normal, but the internal structure deteriorated. That is, cell recruitment was disrupted and co-firing patterns within reactivation events were weakened. Place cells also became less stable over time, especially after rest periods, exactly when they should be strengthened by regeneration.
These neurological disorders affected behavior. Affected mice performed poorly in the maze and repeatedly revisited arms that had already been explored. “We have uncovered the breakdown of how the brain consolidates memories at the level of individual neurons,” said co-first author Dr. Caswell Barry. “What’s surprising is that replay events are still occurring, but they’ve lost their normal structure. It’s not like the brain has stopped trying to consolidate memories; the process itself has gone wrong.”
The research team believes that insights into this mechanism could provide a stepping stone to earlier diagnosis and more targeted treatments. “We hope our findings will help develop tests to detect Alzheimer’s disease early, before extensive damage occurs, or lead to new treatments targeting this regenerative process,” Barry said. “We are currently investigating whether we can manipulate regeneration through the neurotransmitter acetylcholine, which is already a target for drugs used to treat the symptoms of Alzheimer’s disease. By understanding the mechanism better, we hope to make such treatments more effective.”