Exogenous Aβ1-42 monomers rescue memory deficits in presenilin-1 and presenilin-2 conditional double knockout mice.

Emerging evidence challenges the direct causal relationship between amyloid-β (Aβ) deposition and cognitive decline in Alzheimer's disease (AD), as exemplified in presenilin-1 and presenilin-2 conditional double knockout (cDKO) mice which exhibit no amyloid plaques and reduced soluble Aβ1-42 monomers, but paradoxically display AD-like memory deficits. In this study, we hypothesize that reduced soluble Aβ1-42 monomers critically underlie memory dysfunction in cDKO mice. Combining behavioral assessments and in vivo multichannel electrophysiology, we show that cDKO mice exhibit impaired spatial and episodic memory, accompanied by reduced theta oscillation power and theta-gamma phase-amplitude coupling in the dorsal hippocampal CA1. Remarkably, exogenous supplementation of physiological level Aβ1-42 monomers rescued memory deficits and restored neural oscillatory dynamics, while co-administration of the α7-nicotinic acetylcholine receptors (α7-nAChRs) antagonist methyllycaconitine blocked these rescuing effects. Our findings reveal that soluble Aβ1-42 monomers help to sustain hippocampal memory through α7-nAChRs-dependent pathways, thereby contributing toa revised perspective on the roles of Aβ1-42 monomers in cognition and suggesting potential avenues for Aβ-targeted AD treatments.