DOI: 10.1002/alz.080055 ISSN: 1552-5260

Circadian genes in wake‐promoting neurons have a different pattern of expression in Alzheimer’s Disease, Progressive Supranuclear Palsy, and Healthy Controls

Felipe Luiz Pereira, Abhijit Satpati, Anya Raju, Alexander Soloviev, Mihovil Mladinov, Claudia Kimie Suemoto, Renata Elaine Paraizo Leite, Alexander J. Ehrenberg, Thomas C. Neylan, Lea T. Grinberg
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Individuals with neurodegenerative disorders often experience sleep disturbances before showing any other symptoms. Our recent studies found a link between tau‐driven degeneration of wake‐promoting neurons (WPN) and sleep/wake dysfunction in Alzheimer’s disease (AD), which is a shift from the previously held beta‐amyloid centric models for sleep dysfunction. The circadian system regulates WPN, but little is known about the pattern of circadian dysregulation in WPN in AD and other tauopathies. Methodological limitation such as undefined borders and the small size of WPN nuclei makes it challenging to perform such studies. We performed gene expression analysis using the nCounter human neuropathology panel and circadian genes custom code set (Nanostring, USA) to map these changes and inform customized therapies.


RNA was isolated from wake‐promoting areas: locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN) dissected from Formalin‐Fixed Paraffin‐Embedded (FFPE) postmortem brain tissue of 6 AD, 7 progressive supranuclear palsy (PSP), and 5 healthy controls (HC) cases with similar ages at death. RNA expression levels were determined using bead‐based hybridization technology and differential expression analysis was conducted using DESeq2 with Wald statistical test and adding sex as a confounding variable.


We identified differentially expressed circadian genes in WPN across disease conditions vs. HC (Figure 1) and between AD and PSP. Clock/Npas2 genes only have differential expression in PSP (although in different directions in LHA vs. TMN). PER gene families had changes in AD and PSP, but only in LHA and TMN.


Expression of circadian genes is dysregulated in WPN in AD and PSP, but the pattern is considerably different, with some gene families showing opposite directions of regional expression even in the same disease (i.e Clock/Npas2 and Cry). Interestingly, circadian dysregulation in hypothalamic neurons is more significant than in LC, possibly reflecting direct connections between the suprachiasmatic nucleus, the circadian clock, and TMN and LHA. This study supports the utility of fixed‐tissue‐based RNA expression analysis to unveil the molecular basis of sleep dysfunction in neurodegenerative diseases, even considering the complex neuroanatomy of the sleep‐controlling regions. Validation of these findings using multiplex immunohistochemistry and clinicopathological correlations are ongoing.

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