Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates
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Abstract
Alzheimer's Disease (AD) is a neuroinflammatory disease characterized partly by the inability to clear, and subsequent build-up, of amyloid-beta (Aβ). AD has a bi-directional relationship with circadian disruption (CD) with sleep disturbances starting years before disease onset. However, the molecular mechanism underlying the relationship of CD and AD has not been elucidated. Myeloid-based phagocytosis, a key component in the metabolism of Aβ, is circadianly-regulated, presenting a potential link between CD and AD. In this work, we revealed that the phagocytosis of Aβ42 undergoes a daily circadian oscillation. We found the circadian timing of global heparan sulfate proteoglycan (HSPG) biosynthesis was the molecular timer for the clock-controlled phagocytosis of Aβ and that both HSPG binding and aggregation may play a role in this oscillation. These data highlight that circadian regulation in immune cells may play a role in the intricate relationship between the circadian clock and AD.
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Disruptions of the 24-hour endogenous cycle have been associated with an acceleration of both the rate and severity of Alzheimer's disease.
“Furthermore, disruptions of the 24‐hour endogenous cycle have been associated with an acceleration of both the rate and severity of Alzheimer’s disease [41].”
From Ocular light exposure interventions for sleep, circadian rhythms, rest-activity cycles, mood, and cognitive function in older adults: An Overview of Cochrane and non-Cochrane Systematic Reviews (2025) · cites this paper as [41]
The Introduction describes circadian-clock disruption as a consequence, and perhaps a cause, of Alzheimer’s disease. The Discussion reports a correlation and proposes a mechanism involving amyloid accumulation, but it does not establish that circadian disruption accelerates both the rate and severity of the disease. Page numbers are unavailable in our copy. (LLM, conf=0.84)
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“It is reported that regulation of circadian entrainment can control Aβ formation through chronotherapy, thereby alleviating symptoms of AD and inflammatory diseases [70].”
BackgroundDysfunction of circadian and sleep rhythms in the early stages of Alzheimer's disease
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Self-citationCircadian disruption induces sex-specific Alzheimer’s pathophysiology and immune cell reprogrammingPreprint
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Self-citationAstrocytic timekeepers and their influence on brain waste clearance in Alzheimer's disease
Koenders, C. L., Chiu, R. K., Medeiros-Furquim, T., & Bergink, S. (2026) · Neurobiology of Sleep and Circadian Rhythms · doi:10.1016/j.nbscr.2026.100155
- Authors
- Clark, G. T., Yu, Y., Urban, C. A., Fu, G., Wang, C., Zhang, F., Linhardt, R. J., & Hurley, J. M.
- Affiliations
- Rensselaer Polytechnic Institute (US)
- Corresponding author
- Hurley, Jennifer M.
- ORCID
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2022-02-10
- Volume
- 18
- Issue
- 2
- Pages
- e1009994
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC8830681
- OpenAlex
- W4226049253
- Cited by
- 31
- References
- 136
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 3 · 2023: 11 · 2022: 6
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Biomedical Imaging and Bioengineering (U01EB022546)
- National Institute of General Medical Sciences (R35GM128687)
- National Science Foundation (2045674)
- National Institutes of Health (1RF1AG069039, DK111958, CA231074)
- Rensselaer Polytechnic Institute (Startup Funds)
- Warren Alpert Foundation (gift)
- National Institute on Aging (AG057464)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- circadian clock, Alzheimer's disease, amyloid-beta, phagocytosis, heparan sulfate proteoglycans, circadian rhythm disruption, sleep disorders, amyloid-beta 42, myeloid cells, neuroinflammation, amyloid-beta clearance
- MeSH terms
- Alzheimer Disease, Animals, Circadian Rhythm, Disease Models, Animal, Male, Mice, Inbred C57BL, Phagocytosis, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Heparan Sulfate Proteoglycans, Mice, Circadian Clocks, Protein Aggregation, Pathological
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