Interaction of Tau with the Neural Membrane Cortex Is Regulated by Phosphorylation at Sites That Are Modified in Paired Helical Filaments
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The axonal microtubule-associated phosphoprotein tau interacts with neural plasma membrane (PM) components during neuronal development (Brandt, R., Léger, J., and Lee, G. (1995) J. Cell Biol. 131, 1327-1340). To analyze the mechanism and potential regulation of tau's PM association, a method was developed to isolate PM-associated tau using microsphere separation of surface-biotinylated cells. We show that tau's PM association requires an intact membrane cortex and that PM-associated tau and cytosolic tau are differentially phosphorylated at sites detected by several Alzheimer's disease (AD) diagnostic antibodies (Ser(199)/Ser(202), Thr(231), and Ser(396)/Ser(404)). In polar neurons, the association of endogenous tau phosphoisoforms with the membrane cortex correlates with an enrichment in the axonal compartment. To test for a direct effect of AD-specific tau modifications in determining tau's interactions, a phosphomutant that simulates an AD-like hyperphosphorylation of tau was produced by site-directed mutagenesis of Ser/Thr residues to negatively charged amino acids (Glu). These mutations completely abolish tau's association with the membrane cortex; however, the construct retains its capability to bind to microtubules. The data suggest that a loss of tau's association with the membrane cortex as a result of phosphorylation at sites that are modified during disease contributes to somatodendritic tau accumulation, axonal microtubule disintegration, and neuronal death characteristic for AD.
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Prior to initiating the screen, the robustness of the protocol was examined using two well characterized tau kinases, CDK5 and GSK3β, as well as GFP, the negative control.
“Prior to initiating the screen, the robustness of the protocol was examined using two well characterized tau kinases, CDK5 (13) and GSK3 𝛃 (18), as well as GFP, the negative control.”
From An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease (2013) · cites this paper as [18]
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“Prior to initiating the screen, the robustness of the protocol was examined using two well characterized tau kinases, CDK5 (13) and GSK3 (18), as well as GFP, the negative control.”
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Self-citationThe Role of the Lipid Bilayer in Tau Aggregation
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“low Thr231 phosphorylation at the neuron’s cortical membrane [20]), one can argue that cell-sorting mechanisms might be responsible for the lack of interaction of BIN1 with pThr231 Tau in neurons.”
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The Evolution of Tau Phosphorylation and Interactions
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Microtubule Dynamics in Neuronal Development, Plasticity, and Neurodegeneration
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Self-citationThe Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology
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- Authors
- Maas, T., Eidenmüller, J., & Brandt, R.
- Affiliations
- Heidelberg University (DE)
- Corresponding author
- Brandt, Roland
- ORCID
- Brandt, Roland
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-05
- Volume
- 275
- Issue
- 21
- Pages
- 15733-15740
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2061655823
- Cited by
- 226
- References
- 50
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 9 · 2019: 10 · 2018: 10 · 2017: 14 · 2016: 7 · 2015: 17 · 2014: 18 · 2013: 11 · 2012: 14
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 31 7)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau phosphorylation, paired helical filaments, Alzheimer's disease, plasma membrane association, axonal microtubules, tau hyperphosphorylation, neuronal cell death
- MeSH terms
- Actins, Alzheimer Disease, Animals, Cell Membrane, Cytosol, Immunohistochemistry, Microscopy, Electron, Microspheres, Microtubules, Neurons, Phosphorylation, Protein Binding, Transfection, Mutagenesis, Site-Directed, PC12 Cells, tau Proteins, Microscopy, Confocal, Okadaic Acid, Biotinylation, Rats
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