Rescue of impaired hippocampal consolidation in the APP/PS1 mouse model of Alzheimer’s disease after increasing cerebral blood flow

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BACKGROUND: Alzheimer's disease (AD) manifests with early spatial memory impairment and is linked to the degeneration of hippocampal circuits. Hippocampal sharp wave ripples (SWRs) are high-frequency population-burst events that coordinate the reactivation of neural assemblies (groups of neurons that become correlated in their firing patterns during learning) in post-learning sleep, which is the neural basis of memory consolidation. SWRs are reduced in the APP/PS1 mouse model of AD-like pathology. Previously, we showed that cerebral blood flow (CBF) decreases and memory deficits were rescued following treatment with anti-Ly6G antibodies. Here, we examine the potential normalization of hippocampal circuit activity with CBF increase. METHOD: Male, 7-14-month-old APP/PS1 mice and wild-type controls were implanted with 64-channel silicon probes in hippocampal area CA1. Neural activity was recorded during sleep before and after the exploration of an open field. Putative cell types were identified using feature-based classification, and neural assemblies were detected using independent component analysis. RESULT: APP/PS1 mice had reduced magnitude and duration of assembly reactivation in post-task sleep SWRs. After treatment with anti-Ly6G antibodies, which increase CBF and improve memory performance, we found increased reactivation of these assemblies in post-task sleep SWRs, relative to no-treatment controls (Figure 1). CONCLUSION: We found that increasing CBF normalizes neural mechanisms of memory consolidation that are altered in AD mouse models, supporting the development of treatment approaches to increase CBF in AD.

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