Neurology Central

Defects in memory replay critical to role of apoE4 in Alzheimer’s disease

Researchers at the Gladstone Institutes (CA, USA) have demonstrated that apoE4 alters GABAergic interneuron activity in the hippocampus by causing defects in memory replay function, which is a critical process in memory consolidation. The findings were published recently in Neuron.

Presence of apoE4 is the main genetic risk factor for Alzheimer’s disease (AD), present in approximately 65–80% of AD patients, however, the associated mechanism of cognitive impairment has remained unclear.

The team involved in the current study observed that apoE4 affects two kinds of hippocampal activity vital to memory processes –sharp wave ripples (SWRs) and consequential slow gamma activity. During SWRs, experiences are replayed in order to maintain the memory of them and the slow gamma activity accompanies the ripples to ensure fidelity of the memory replay.

“When we experience something new, cells in the hippocampus fire in a particular order. Later, these same cells fire over and over again in the same order to replay the event, which helps consolidate the memory so we don’t forget it,” described Anna Gillespie (formerly Gladstone Institutes). “Slow gamma activity that occurs during the ripples organizes the firing of these cells. If this activity is disrupted, the playback will be disorganized, compromising the memory.”

Researchers utilized apo-E4 knockin mouse models in order to investigate how apoE4 may cause the age-related memory and learning impairments characteristic of AD. Human apoE4 was utilized in order to cause age-related damage of memory and learning as well as degeneration of GABAergic interneurons, located in the hippocampal dentate gyrus.

Perturbation in important hippocampal mechanisms involved in memory replay processes – SWRs – was observed in aged apoE4 mice. A lower abundance of SWRs were observed in aged apoE4 mice relative to apoE3 mice.

Aged apoE4 mice also exhibited reduced slow gamma activity during SWRs. The reduction in slow gamma activity was rescued through elimination of apoE4 in GABAergic interneurons, however, the abundance of SWRs remained the same subsequent to this elimination.

SWR abundance was also reduced in young as well as aged apoE4 mice while slow gamma activity during SWRs was only observed in aged apoE4 mice, indicating that slow gamma activity may be a significant contributing factor to apoE4-related memory and learning impairment. That is to say that the neuronal coordination of memory replay rather than the number of ‘replay’ SWR events could be crucial for memory reinforcement.

“Our research suggests that disrupted slow gamma activity during ripples is a major consequence of apoE4 expression that likely impairs memory consolidation,” remarked Yadong Huang (Gladstone Institutes). “With this knowledge, we can now work toward correcting or restoring slow gamma activity in the hippocampus to prevent or alleviate memory loss in Alzheimer’s disease.”

Sources: Gladstone Institutes Press Release; Gillespie AK, Jones EA, Lin Y-H et al. Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples. Neuron doi:10.1016/j.neuron.2016.04.009 (2016) (Epub ahead of print).