Journal article
Reconstructed cell-type-specific rhythms in human brain link Alzheimer's pathology, circadian stress, and ribosomal disruption
Neuron (Cambridge, Mass.), v 113(17), pp 2822-2838
03 Sep 2025
PMID: 40774247
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer's disease (AD) disrupts behavioral circadian rhythms, but its effects on molecular rhythms in the human brain are poorly understood. Using single-nucleus RNA sequencing (snRNA-seq) from post-mortem cortical samples, we informatically estimated the relative circadian phases of 409 persons with and without AD dementia, reconstructing circadian expression profiles across cell types. Although core clock rhythms were preserved in AD, many cell-type-specific circadian outputs were disrupted. Rhythms in ribosomal biogenesis and oxidative phosphorylation were dampened across cell types. Similar losses in ribosomal gene expression rhythms were observed in amyloid precursor protein/presenilin 1 (APP/PS1) mice, which showed further reductions in ribosomal protein expression and polysome-mediated translation after circadian desynchrony. Exploratory computational modeling reveals that altered translation may contribute to the increased circadian variability seen in AD patients. These findings reveal altered cell-type-specific circadian output rhythms in the brains of AD-affected patients and highlight disrupted ribosomal rhythms as a feature of AD.
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Details
- Title
- Reconstructed cell-type-specific rhythms in human brain link Alzheimer's pathology, circadian stress, and ribosomal disruption
- Creators
- Henry C. Hollis - Drexel UniversityAshish Sharma - Washington University in St. LouisPatrick W. Sheehan - Washington University in St. LouisLeonard B. Maggi Jr - College Station Medical CenterJason D. Weber - Washington University in St. LouisJan A. Hammarlund - Drexel UniversityDavid A. Bennett - Rush University Medical CenterVilas Menon - Columbia University Irving Medical CenterErik S. Museik - College Station Medical CenterRon C. Anafi (Corresponding Author) - University of Pennsylvania
- Publication Details
- Neuron (Cambridge, Mass.), v 113(17), pp 2822-2838
- Publisher
- Elsevier
- Number of pages
- 17
- Grant note
- A2024031F / BrightFocus Foundation R01AG17917 / NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) U01AG46152; NIH U01AG61356 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering and Science
- Web of Science ID
- WOS:001568341200005
- Scopus ID
- 2-s2.0-105012607428
- Other Identifier
- 991022197397004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences