Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer’s Disease
Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer’s Disease
Abstract In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment 1,2. Neuronal hyperactivity is observed early in AD 3,4. Here, we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the AppNL-G-F humanized knock-in mouse model for AD 5, but ultimately fail to maintain neuronal activity at set-point. Spatial transcriptomic analysis in CA1 during the homeostatic response identifies the Melanin-Concentrating Hormone (MCH)-encoding gene. MCH is expressed in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory 6. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in AppNL-G-F mice, disrupting sleep-dependent homeostatic plasticity and stability of neuronal activity in CA1. Finally, we find perturbed MCH-axon morphology in CA1 early in AppNL-G-F mice and in AD patients. Our work identifies dysregulation of the MCH-system as a key player in aberrant neuronal activity in the early stages of AD.
Craessaerts Katleen、Vandenbempt Joris、van Boekholdt Luuk、?zturan G?khan、Vanderlinden Jeroen、Davie Kristofer、Thal Dietmar Rudolf、de Wit Joris、Thrupp Nicky、Poovathingal Suresh、Chen Wei-Ting、Calafate Sara、Creemers Eline、Wierda Keimpe、Lu Ashley、Fiers Mark、De Strooper Bart
VIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteKU Leuven, Department of OtorhinolaryngologyVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteDepartment of Imaging and Pathology, Laboratory of Neuropathology, Leuven Brain Institute, KU-Leuven||Department of Pathology, UZ LeuvenVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain InstituteVIB Center for Brain & Disease Research||KU Leuven, Department of Neurosciences, Leuven Brain Institute||UK Dementia Research Institute (UK DRI@UCL) at University College London
神经病学、精神病学基础医学生理学
Craessaerts Katleen,Vandenbempt Joris,van Boekholdt Luuk,?zturan G?khan,Vanderlinden Jeroen,Davie Kristofer,Thal Dietmar Rudolf,de Wit Joris,Thrupp Nicky,Poovathingal Suresh,Chen Wei-Ting,Calafate Sara,Creemers Eline,Wierda Keimpe,Lu Ashley,Fiers Mark,De Strooper Bart.Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer’s Disease[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.05.21.445007.点此复制
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