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

Early degeneration of basal forebrain cholinergic neurons is a key feature of Alzheimer’s disease (AD). Here, we looked genetically at the intersection of amyloid pathology and the cholinergic system. We expressed in mice of both sexes an App ^NL-G-F allele, harboring familial AD mutations, specifically in cholinergic medial septum (MS) neurons, and compared the phenotype to mice with global App ^NL-G-F expression. Over the course of 14 months, as mice reached late middle age, targeted expression led to the loss of about one-third of MS cholinergic neurons and widespread amyloid deposition in their terminal fields, especially in the hippocampus and, to a lesser extent, on blood vessels. This selective vulnerability of ageing cholinergic cells to amyloid, markedly reduced REM sleep and caused cognitive and emotional alterations resembling those in mice with the mutation expressed throughout the brain. Mice with global App ^NL-G-F expression also had a previously unreported selective death of about 20% of their medial septal cholinergic cells. Although the broadcasting of amyloid by medial septal cholinergic cells is a notable feature, and potentially important in human pathology, selective genetic lesioning of about one third of the medial septal cholinergic cells, independently of amyloid, gave the same REM sleep, cognitive and emotional phenotypes. Thus, it is the killing of the cholinergic cells by amyloid, and therefore the missing acetylcholine, and not the secreted/deposited amyloid in the hippocampus and other areas that is the critical feature. These findings underscore the interest in revitalizing the classic cholinergic hypothesis of AD. Restricting pathological amyloid expression to MS cholinergic neurons, so that their health is compromised by amyloid, is sufficient to reproduce many AD- like symptoms, highlighting the critical role of these cells in early AD pathogenesis, REM sleep regulation, emotion and cognition.