Nollet M, Ba W, Soto BA, Yin C, Lignos L, Jovic K, Vyssotski AL, Yustos R, Franks NP, Wisden W (2025) 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. bioRxiv 2025.07.09.663930. doi: 10.1101/2025.07.09.663930
Objective: To look genetically at the intersection of amyloid pathology and the cholinergic system in Alzheimer’s disease (AD).
Summary: 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, independent 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.
Usage: Cholinergic neurons throughout the forebrain in mice were lesioned with mu p75-SAP. The loss of cholinergic innervation exacerbated neurovascular impairments and cerebral amyloid angiopathy progression in the cortex and hippocampus
Related Products: mu p75-SAP (Cat. #IT-16)