Impaired sharp-wave ripple coordination between the medial entorhinal cortex and hippocampal CA1 of knock-in model of Alzheimer's disease

Clinical evidence suggests that the entorhinal cortex is a primary brain area triggering memory impairments in Alzheimer's disease (AD), but the underlying brain circuit mechanisms remain largely unclear. In healthy brains, sharp-wave ripples (SWRs) in the hippocampus and entorhinal cortex play a critical role in memory consolidation. We tested SWRs in the MEC layers 2/3 of awake amyloid precursor protein knock-in (APP-KI) mice, recorded simultaneously with SWRs in the hippocampal CA1. We found that MEC -> CA1 coordination of SWRs, found previously in healthy brains, was disrupted in APP-KI mice even at a young age before the emergence of spatial memory impairments. Intriguingly, long-duration SWRs critical for memory consolidation were mildly diminished in CA1, although SWR density and amplitude remained intact. Our results point to SWR incoordination in the entorhinal-hippocampal circuit as an early network symptom that precedes memory impairment in AD.

Automated summary

Clinical evidence suggests that disruptions in the coordination of sharp-wave ripples (SWRs) between the entorhinal cortex and hippocampal CA1 may serve as an early network symptom that precedes memory impairment in Alzheimer's disease. This study found that the coordination of SWRs between the medial entorhinal cortex (MEC) layers and CA1 was disrupted in amyloid precursor protein knock-in (APP-KI) mice, even before the emergence of spatial memory impairments. These findings provide insight into the underlying brain circuit mechanisms of memory impairments in Alzheimer's disease.