Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer’s Disease

In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment [1][1],[2][2]. Neuronal hyperactivity is observed early in AD [3][3],[4][4]. Here, we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the App NL-G-F humanized knock-in mouse model for AD [5][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][6]. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in App NL-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 App NL-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. ### Competing Interest Statement D.R.T. received speaker honorarium from Novartis Pharma Basel (Switzerland) and Biogen (USA), travel reimbursement from GE-Healthcare (UK), and UCB (Belgium), and collaborated with GE-Healthcare (UK), Novartis Pharma Basel (Switzerland), Probiodrug (Germany), and Janssen Pharmaceutical Companies (Belgium). B.D.S. is consultant for Eisai, Abbvie, K5/Muno; co-founder of Augustine Tx; founder and shareholder of K5/Muno. J.d.W. is co-founder and scientific advisory board member of Augustine Tx. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6