Decreased Orexin Receptor 1 mRNA Expression in the Locus Coeruleus in Both Tau Transgenic rTg4510 and Tau Knockout Mice and Accompanying Ascending Arousal System Tau Invasion in rTg4510

Article type: Research Article

Authors: Keenan, Ryan J.^{a; b; †} | Oberrauch, Sara^{a; b; †} | Bron, Romke^c | Nowell, Cameron J.^c | Challis, Leesa M.^a | Hoyer, Daniel^{a; b; d} | Jacobson, Laura H.^{a; b; e; *}

Affiliations: [a] Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia | [b] Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia | [c] Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia | [d] Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA | [e] Melbourne Dementia Research Centre, University of Melbourne, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia

Correspondence: [*] Correspondence to: Laura H. Jacobson, Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Sleep/wake disturbances (e.g., insomnia and sleep fragmentation) are common in neurodegenerative disorders, especially Alzheimer’s disease (AD) and frontotemporal dementia (FTD). These symptoms are somewhat reminiscent of narcolepsy with cataplexy, caused by the loss of orexin-producing neurons. A bidirectional relationship between sleep disturbance and disease pathology suggests a detrimental cycle that accelerates disease progression and cognitive decline. The accumulation of brain tau fibrils is a core pathology of AD and FTD-tau and clinical evidence supports that tau may impair the orexin system in AD/FTD. This hypothesis was investigated using tau mutant mice. Objective:To characterize orexin receptor mRNA expression in sleep/wake regulatory brain centers and quantify noradrenergic locus coeruleus (LC) and orexinergic lateral hypothalamus (LH) neurons, in tau transgenic rTg4510 and tau–/– mice. Methods:We used i n situ hybridization and immunohistochemistry (IHC) in rTg4510 and tau–/– mice. Results:rTg4510 and tau–/– mice exhibited a similar decrease in orexin receptor 1 (OX1R) mRNA expression in the LC compared with wildtype controls. IHC data indicated this was not due to decreased numbers of LC tyrosine hydroxylase-positive (TH) or orexin neurons and demonstrated that tau invades TH LC and orexinergic LH neurons in rTg4510 mice. In contrast, orexin receptor 2 (OX2R) mRNA levels were unaffected in either model. Conclusion:The LC is strongly implicated in the regulation of sleep/wakefulness and expresses high levels of OX1R. These findings raise interesting questions regarding the effects of altered tau on the orexin system, specifically LC OX1Rs, and emphasize a potential mechanism which may help explain sleep/wake disturbances in AD and FTD.

Keywords: Alzheimer’s disease, frontotemporal dementia, in situ hybridization, locus coeruleus, orexin, orexin receptor, rTg4510, sleep, tau

DOI: 10.3233/JAD-201177

Journal: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 693-708, 2021