Modeling the prodromal phase of Alzheimer’s disease: Selective amyloid-driven failure of cholinergic medial septal neurons perturbs REM sleep, cognition, emotion, and broadcasts pathology in aging mice (2026)

Abstract

In humans, decreases in rapid eye movement sleep (REMS) strongly predict Alzheimer’s disease (AD), alongside early degeneration of basal forebrain cholinergic neurons. We examined how β-amyloid pathology gradually erodes mouse cholinergic neurons. The familial App^NL-G-F allele was selectively expressed in medial septal (MS) cholinergic neurons of both sexes and compared with mice with global App^NL-G-F expression and selective genetic lesions of MS cholinergic cells. By 14 months, targeted App^NL-G-F allele expression had caused loss of 25% of MS cholinergic neurons and produced amyloid deposition in their terminal fields, particularly the hippocampus. REMS was reduced, together with cognitive and emotional alterations mirroring phenotypes in global mutants, which also showed selective MS cholinergic cell loss. Genetic lesioning of MS cholinergic cells recapitulated most phenotypes, identifying cholinergic loss, not amyloid deposition, as a probable cause of these phenotypes. Nevertheless, broadcasted amyloid from MS cholinergic neurons likely induced hippocampal astrocyte activation and epileptiform spikes.