Work

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

Year: 2025

Type: preprint

Abstract: SUMMARY 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. Highlights Amyloid in medial septum causes cholinergic neuron loss and Alzheimer’s symptoms Amyloid from medial septal axons may trigger pathology in distant brain regions Loss of acetylcholine, not amyloid spread, drives REM sleep and cognitive deficits Broadcasted septal amyloid induces hippocampal astrogliosis and epileptiform spikes GRAPHICAL ABSTRACT

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2025.07.09.663930