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Erik Musiek

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Erik Musiek is an American neurologist and chronobiologist. His research focuses on the molecular mechanisms of neurodegeneration, the role of circadian rhythms in Alzheimer’s disease, and potential therapeutic interventions. He is the Charlotte & Paul Hagemann Professor of Neurology at Washington University in St. Louis.[1] In addit ion to his research, he is also a practicing neurologist specializing in Alzheimer’s Disease and has written extensively on anti-amyloid antibody therapies.[2][3][4][5]

Early life and clinical career

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Musiek is from Hanover, New Hampshire.[1] He completed his Bachelor of Science in Biological Psychology at the College of William and Mary in 1999. He went on to complete a PhD in Pharmacology at Vanderbilt University in 2005 and a Doctor of Medicine (M.D.) degree from Vanderbilt University in 2007. Musiek completed a residency in neurology at the University of Pennsylvania in 2011, then pursued a fellowship in Alzheimer’s Disease Research at Washington University in St. Louis in 2012. As of 2014, Musiek is an assistant professor of neurology and the principal investigator at the Musiek Lab at Washington University in St. Louis.[6] In his clinical practice, Musiek is a practicing physician specializing in treating patients with Alzheimer's Disease and other neurodegenerative diseases.

Research and career

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Research on clock genes and neurodegenerative diseases

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Musiek and colleagues at Washington University School of Medicine in St. Louis analyzed the link between circadian clocks, sleep, and neurodegeneration using mice lacking the key clock gene, BMAL1, in the cortex and hippocampus.[7]

The results showed disrupted rhythms of clock genes in most of the brain. The Musiek lab showed that the mice developed signs of pathology, including loss of synapses, damage from free radicals, and inflammation. Notably, there was reduced activity in genes associated with the defense against free radicals, suggesting that the increase in free radicals contributed to brain damage. Furthermore, Musiek reports that the disruption of BMAL1 leads to premature nerve cell deterioration in mice.[8] Musiek identified that BMAL1 is important in fending off age-related brain decay by protecting the brain from free radicals that lead to oxidative stress.

As the BMAL1 knockout mice aged, their brains displayed degenerative features akin to human brain diseases, such as the accumulation of toxic proteins (e.g., β-amyloid and α-synuclein).[9] These features were also observed when CLOCK and NPAS2 were deleted, which are circadian genes that work closely with BMAL1.[10] Conversely, these effects do not appear after the deletion of the clock genes PER1 and PER2. Musiek discovered that astrocytes were more active in mice lacking BMAL1, as BMAL1 within astrocytes can directly control astrocyte reactivity and protein degradation.[10][11] His lab also showed that another clock gene, REV-ERBα, can regulate glial activity and neuroinflammation in the brain.[12][13]

Studies of YKL-40 in Alzheimer's Disease

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Musiek and colleagues discovered that YKL-40, a known biomarker for Alzheimer’s disease (AD), was regulated by circadian genes like BMAL1.[14] Their research showed that knocking out the Chi3l1 gene, which encodes YKL-40, led to reduced amyloid plaque formation via increased phagocytosis by astrocytes and microglia.[14] Mouse models prone to amyloid plaques but lacking YKL-40 exhibited lower plaque accumulation and enhanced microglial responses.[15] Although Chi3l1 mRNA did not oscillate on a 24-hour basis, it was downregulated in BMAL1 knockout mice and upregulated in PER1 and PER2 knockouts. This suggests that the circadian regulation of YKL-40 plays a role in AD pathology, particularly in modulating glial activity and amyloid beta clearance.[14][15]

Studies of circadian rhythm fragmentation in Alzheimer’s Disease

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Musiek and his colleague David Holtzman published a scientific review discussing how circadian rhythm disruption may influence disease progression found a diurnal oscillation of Aβ in the sleep-wake cycle. Furthermore, they discovered that sleep deprivation impairs metabolite clearance, exacerbating Aβ pathology.[16] In a 2018 study, Musiek and colleagues examined 189 cognitively normal older adults (> 45 years old) to monitor their circadian rhythms and detect amyloid deposition via PET scans.[17][18] After removing confounding variables, they identified a positive correlation between circadian irregularities and amyloid plaque accumulation.[19]

Even with this research, there are still notable gaps in the link between circadian rhythms and AD pathogenesis.[20] The molecular mechanisms linking sleep to known Alzheimer's biomarkers, such as amyloid plaques, are largely unknown.[20] Musiek urged that the specific aspects of sleep most critical for Alzheimer's pathology must be targeted for therapies.[20] Musiek also emphasized new methods for making circadian measurements, including actigraphy and home-based technologies.[20] He hopes that these methods may be adopted after extensive validation, along with continued investigation of sleep-circadian biomarkers.[20]

Awards and recognition

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Musiek is board-certified in neurology and co-Director of the Center on Biological Rhythms and Sleep. He received the Kopolow Award for Aging Research and is a member of the American Society for Clinical Investigation. He has published more than 60 peer-reviewed papers and serves on multiple NIH study sections and national advisory committees.[6][1]

References

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  1. ^ a b c "PEOPLE". musieklab. Retrieved April 2, 2025.
  2. ^ Musiek, Erik S.; Gomez-Isla, Teresa; Holtzman, David M. (October 15, 2021). "Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside". Journal of Clinical Investigation. 131 (20). doi:10.1172/JCI154889. ISSN 1558-8238. PMC 8516468. PMID 34651585.
  3. ^ Musiek, Erik S.; Morris, John C. (February 1, 2021). "Possible Consequences of the Approval of a Disease-Modifying Therapy for Alzheimer Disease". JAMA Neurology. 78 (2): 141–142. doi:10.1001/jamaneurol.2020.4478. ISSN 2168-6149. PMID 33252672.
  4. ^ Musiek, Erik S.; Bennett, David A. (October 6, 2021). "Aducanumab and the "post-amyloid" era of Alzheimer research?". Neuron. 109 (19): 3045–3047. doi:10.1016/j.neuron.2021.09.007. PMC 9308468. PMID 34582783.
  5. ^ Musiek, Erik S.; McDade, Eric; Holtzman, David M. (2023). "Lecanamab Ushers in a New Era of Anti-Amyloid Therapy for Alzheimer's Disease". Annals of Neurology. 93 (5): 877–880. doi:10.1002/ana.26643. ISSN 1531-8249. PMID 36919987.
  6. ^ a b "Erik Musiek, MD, PhD". WashU Medicine Physicians. Retrieved April 2, 2025.
  7. ^ Musiek, Erik S.; Lim, Miranda M.; Yang, Guangrui; Bauer, Adam Q.; Qi, Laura; Lee, Yool; Roh, Jee Hoon; Ortiz-Gonzalez, Xilma; Dearborn, Joshua T.; Culver, Joseph P.; Herzog, Erik D.; Hogenesch, John B.; Wozniak, David F.; Dikranian, Krikor; Giasson, Benoit I. (December 25, 2013). "Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration". The Journal of Clinical Investigation. 123 (12): 5389–5400. doi:10.1172/JCI70317. ISSN 1558-8238. PMC 3859381. PMID 24270424.
  8. ^ Musiek, Erik S.; Lim, Miranda M.; Yang, Guangrui; Bauer, Adam Q.; Qi, Laura; Lee, Yool; Roh, Jee Hoon; Ortiz-Gonzalez, Xilma; Dearborn, Joshua T.; Culver, Joseph P.; Herzog, Erik D.; Hogenesch, John B.; Wozniak, David F.; Dikranian, Krikor; Giasson, Benoit I. (December 2, 2013). "Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration". The Journal of Clinical Investigation. 123 (12): 5389–5400. doi:10.1172/JCI70317. ISSN 0021-9738. PMC 3859381. PMID 24270424.
  9. ^ Makin, Simon. "Why Sleep Disorders May Precede Parkinson's and Alzheimer's". Scientific American. Retrieved April 7, 2025.
  10. ^ a b Lananna, Brian V.; Nadarajah, Collin J.; Izumo, Mariko; Cedeño, Michelle R.; Xiong, David D.; Dimitry, Julie; Tso, Chak Foon; McKee, Celia A.; Griffin, Percy; Sheehan, Patrick W.; Haspel, Jeffery A.; Barres, Ben A.; Liddelow, Shane A.; Takahashi, Joseph S.; Karatsoreos, Ilia N. (October 2018). "Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1". Cell Reports. 25 (1): 1–9.e5. doi:10.1016/j.celrep.2018.09.015. PMC 6221830. PMID 30282019.
  11. ^ McKee, Celia A.; Polino, Alexander J.; King, Melvin W.; Musiek, Erik S. (May 16, 2023). "Circadian clock protein BMAL1 broadly influences autophagy and endolysosomal function in astrocytes". Proceedings of the National Academy of Sciences. 120 (20): e2220551120. Bibcode:2023PNAS..12020551M. doi:10.1073/pnas.2220551120. ISSN 0027-8424. PMC 10194014. PMID 37155839.
  12. ^ Griffin, Percy; Dimitry, Julie M.; Sheehan, Patrick W.; Lananna, Brian V.; Guo, Chun; Robinette, Michelle L.; Hayes, Matthew E.; Cedeño, Michelle R.; Nadarajah, Collin J.; Ezerskiy, Lubov A.; Colonna, Marco; Zhang, Jinsong; Bauer, Adam Q.; Burris, Thomas P.; Musiek, Erik S. (March 12, 2019). "Circadian clock protein Rev-erbα regulates neuroinflammation". Proceedings of the National Academy of Sciences of the United States of America. 116 (11): 5102–5107. Bibcode:2019PNAS..116.5102G. doi:10.1073/pnas.1812405116. ISSN 1091-6490. PMC 6421453. PMID 30792350.
  13. ^ Griffin, Percy; Sheehan, Patrick W.; Dimitry, Julie M.; Guo, Chun; Kanan, Michael F.; Lee, Jiyeon; Zhang, Jinsong; Musiek, Erik S. (December 1, 2020). "REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis". eLife. 9: e58765. doi:10.7554/eLife.58765. ISSN 2050-084X. PMC 7728439. PMID 33258449.
  14. ^ a b c "Not Just a Biomarker: YKL-40 Links Glial Clock to Amyloidosis | ALZFORUM". www.alzforum.org. Archived from the original on September 7, 2024. Retrieved April 2, 2025.
  15. ^ a b Bhandari, Tamara (December 16, 2020). "Protein involved in removing Alzheimer's buildup linked to circadian rhythm". WashU Medicine. Retrieved April 2, 2025.
  16. ^ Musiek, Erik S.; Xiong, David D.; Holtzman, David M. (March 13, 2015). "Sleep, circadian rhythms, and the pathogenesis of Alzheimer Disease". Exp Mol Med. 47 (3): e148. doi:10.1038/emm.2014.121. PMC 4351409. PMID 25766617.
  17. ^ "Faulty Brain Clocks Precede Alzheimer's, May Drive Pathology".
  18. ^ X (January 30, 2018). "Sleep cycle troubles may be early sign of Alzheimer's disease". Los Angeles Times. Retrieved April 2, 2025.
  19. ^ "Circadian rhythm abnormalities present in preclinical Alzheimer's disease". www.healio.com. Retrieved April 2, 2025.
  20. ^ a b c d e Musiek, Erik S.; Ju, Yo-El S. (September 1, 2022). "Targeting Sleep and Circadian Function in the Prevention of Alzheimer Disease". JAMA Neurology. 79 (9): 835–836. doi:10.1001/jamaneurol.2022.1732. ISSN 2168-6149. PMC 10437079. PMID 35816332.
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