Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer’s disease
Authors listSara Calafate Gökhan Özturan Nicola Thrupp Jeroen Vanderlinden Luísa Santa-Marinha Rafaela Morais-Ribeiro Antonella Ruggiero Ivan Bozic Thomas Rusterholz Blanca Lorente-Echeverría Marcelo Dias Wei-Ting Chen Mark Fiers Ashley Lu Ine Vlaeminck Eline Creemers Katleen Craessaerts Joris Vandenbempt Luuk van Boekholdt Suresh Poovathingal Kristofer Davie Dietmar Rudolf Thal Keimpe Wierda Tiago Gil Oliveira Inna Slutsky Antoine Adamantidis Bart De Strooper Joris de Wit
Early Alzheimer’s disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep–active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions.