Naturally Occurring Soluble Aβ Oligomers Induce State-Dependent Hippocampal Circuit Dysfunction in Nontransgenic Mice

Abstract Amyloid-beta (Aβ) plaques are a hallmark of Alzheimer’s Disease (AD), but the modest cognitive benefit of anti-amyloid antibodies despite plaque clearance implicates plaque-independent mechanisms in disease progression. Aβ oligomers (AβOs), a toxic soluble species, disrupt synapses, but their effects on hippocampal circuit function in vivo remain unclear. We tested whether naturally occurring AβOs are sufficient to disrupt hippocampal circuit function independent of plaques in nontransgenic mice, infusing wild-type culture medium (WtCM), Tg2576-derived culture medium containing naturally occurring human AβOs (TgCM), or Aβ-immunodepleted TgCM into CA1. We recorded hippocampal calcium activity and local field potentials as mice explored a linear track and during post-learning quiet wakefulness. During exploratory behavior, TgCM impaired theta-gamma coupling versus WtCM, without affecting running, calcium activity, or place cells. During quiet wakefulness, TgCM reduced calcium activity versus WtCM, without a detectable effect on reactivation, delta oscillations, or sharp wave ripples. Aβ depletion prevented both effects. These results suggest that AβO-induced circuit disruption depends on behavioral state, implicating distinct vulnerabilities in encoding and offline processing. Because these effects occurred in nontransgenic hippocampus without amyloid plaques or chronic transgene expression, soluble AβOs are sufficient to disrupt memory-relevant circuit function and represent a therapeutic target upstream of plaque clearance.