The selective amyloid-driven failure of cholinergic medial septal neurons in aging mice perturbs REM sleep, cognition and emotion, and broadcasts amyloid to other brain regions

Abstract

In humans, decreases in rapid eye movement sleep (REMS) strongly predict Alzheimers disease (AD), alongside early degeneration of basal forebrain cholinergic neurons. We examined how {beta}-amyloid pathology gradually erodes mouse cholinergic neurons. The familial AppNL-G-F allele was selectively expressed in medial septal (MS) cholinergic neurons of both sexes and compared with mice with global AppNL-G-F expression and selective genetic lesions of MS cholinergic cells. By 14 months, targeted AppNL-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. HighlightsO_LIAmyloid in medial septum causes cholinergic neuron loss and Alzheimers symptoms C_LIO_LIAmyloid from medial septal axons may trigger pathology in distant brain regions C_LIO_LILoss of acetylcholine, not amyloid spread, drives REM sleep and cognitive deficits C_LIO_LIBroadcasted septal amyloid induces hippocampal astrogliosis and epileptiform spikes C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/663930v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@147275dorg.highwire.dtl.DTLVardef@69745borg.highwire.dtl.DTLVardef@1560ddborg.highwire.dtl.DTLVardef@a7d8d6_HPS_FORMAT_FIGEXP M_FIG C_FIG