Bace1 modulates myelination in the central and peripheral nervous system
Abstract
Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the beta-secretase site. Apart from this cleavage, the functional importance of Bace1 in other physiological events is unknown. We show here that Bace1 regulates the process of myelination and myelin sheath thickness in the central and peripheral nerves. In Bace1-null mice, the process of myelination was delayed and myelin thickness was markedly reduced, indicating that genetic deletion of Bace1 causes hypomyelination. Bace1-null mice also showed altered neurological behaviors such as elevated pain sensitivity and reduced grip strength. Further mechanistic studies showed an altered neuregulin-Akt signaling pathway in Bace1-null mice. Full-length neuregulin-1 was increased and its cleavage product was decreased in the CNS of Bace1-null mice. Furthermore, phosphorylated Akt was also reduced. Based upon these and previous studies, we postulate that neuronally enriched Bace1 cleaves neuregulin-1 and that processed neuregulin-1 regulates myelination by means of phosphorylation of Akt in myelin-forming cells.
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Tamoxifen administration between the ages of 4 and 8 weeks, after the majority of developmental myelination has taken place, avoids developmental and early postnatal effects of BACE1 knockout on myelin.
“To avoid developmental and early postnatal effects of BACE1 knockout on myelin [34], we used tamoxifen inducible Cre lines, with tamoxifen administered between the ages of 4 and 8 weeks (after the majority of developmental myelination has taken place [35]), according to standard protocols [36].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [34]
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Hrabinova, M., Pejchal, J., Kucera, T., Jun, D., Schmidt, M., & Soukup, O. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200503023323 · Cited by 28 · see citing works
Mole, J. P., Fasano, F., Evans, J., Sims, R., Hamilton, D. A., Kidd, E., & Metzler-Baddeley, C. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.06.014 · Cited by 20 · see citing works
BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex
Petrus, E., & Lee, H.-K. (2014) · Neural Plasticity · doi:10.1155/2014/128631 · Cited by 19 · see citing works
- Authors
- Hu, X., Hicks, C. W., He, W., Wong, P., Macklin, W. B., Trapp, B. D., & Yan, R.
- Affiliations
- Cleveland Clinic (US)
- Johns Hopkins University (US)
- Corresponding author
- Yan, Riqiang
- Venue
- Nature Neuroscience
- Published
- 2006-11-12
- Volume
- 9
- Issue
- 12
- Pages
- 1520-1525
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1989453114
- Cited by
- 608
- References
- 39
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 12 · 2023: 15 · 2022: 22 · 2021: 22 · 2020: 24 · 2019: 25 · 2018: 24 · 2017: 31 · 2016: 45 · 2015: 32 · 2014: 45 · 2013: 46 · 2012: 53
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- BACE1, beta-secretase, myelination, hypomyelination, myelin thickness, neuregulin-1, Akt signaling, pain sensitivity, grip strength, central nervous system, peripheral nervous system, oligodendrocytes
- MeSH terms
- Animals, Central Nervous System, Myelin Sheath, Nerve Fibers, Myelinated, Signal Transduction, Aspartic Acid Endopeptidases, Protein Serine-Threonine Kinases, Peripheral Nervous System, Mice, Knockout, Neuregulin-1, Mice, Amyloid Precursor Protein Secretases
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