Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo
Abstract
Hyperphosphorylated forms of the microtubule-associated protein (MAP) tau accumulate in Alzheimer's disease and related tauopathies and are thought to have an important role in neurodegeneration. However, the mechanisms through which phosphorylated tau induces neurodegeneration have remained elusive. Here, we show that tau-induced neurodegeneration is associated with accumulation of filamentous actin (F-actin) and the formation of actin-rich rods in Drosophila and mouse models of tauopathy. Importantly, modulating F-actin levels genetically leads to dramatic modification of tau-induced neurodegeneration. The ability of tau to interact with F-actin in vivo and in vitro provides a molecular mechanism for the observed phenotypes. Finally, we show that the Alzheimer's disease-linked human beta-amyloid protein (Abeta) synergistically enhances the ability of wild-type tau to promote alterations in the actin cytoskeleton and neurodegeneration. These findings raise the possibility that a direct interaction between tau and actin may be a critical mediator of tau-induced neurotoxicity in Alzheimer's disease and related disorders.
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Pathologic tau causes an increase in actin stabilization that inhibits association of the fission protein Drp1 with mitochondria, leading to mitochondrial elongation and production of reactive oxygen species.
“Pathologic tau causes an increase in actin stabilization18 that inhibits association of the fission protein Drp1 with mitochondria, leading to mitochondrial elongation and the production of reactive oxygen species44.”
From Tau promotes neurodegeneration through global chromatin relaxation (2014) · cites this paper as [18]
Many disease-associated phosphorylated residues cluster within the proline-rich region of the N-terminal projection domain and the C-terminal region adjacent to the microtubule-binding repeats.
“Many disease-associated phosphorylated residues cluster within the proline-rich region of the N-terminal projection domain and the C-terminal region adjacent to the microtubule-binding repeats (Fulga et al., 2007; Steinhilb et al., 2007; Hoover et al., 2010; Wesseling et al., 2020).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Fulga et al., 2007
The 14 disease-associated mutations used here to mimic hyperphosphorylation are located within these regions.
“The 14 disease-associated mutations used here to mimic hyperphosphorylation are located within these regions”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Fulga et al., 2007
Pathogenic forms of Tau have been connected to the formation of actin-rich rods, which were found to induce neurodegeneration in Drosophila neurons.
“Pathogenic forms of Tau have been connected to the formation of actin-rich rods56, which were found to induce neurodegeneration in Drosophila neurons22.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [22]
Binding of Tau and MAP2 to filamentous actin results in actin cross-linking and filament bundling.
“Binding of Tau and MAP2 to filamentous actin results in actin cross-linking and filament bundling5, 6, 14, 22, 40–43.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [22]
The interaction of Tau with actin is important for neurite outgrowth and synaptic dysfunction.
“The interaction of Tau with actin is important for neurite outgrowth and synaptic dysfunction11, 12, 22.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [22]
Tau-induced neurotoxicity is associated with increased F-actin levels.
“In addition, Tau-induced neurotoxicity is associated with increased F-actin levels22, and Tau-induced remodeling of the actin cytoskeleton can cause plasma membrane blebbing57.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [22]
Tau neurotoxicity correlates with alterations of actin organization in animal models of Alzheimer's disease.
“Furthermore, tau neurotoxicity correlates with alterations of actin organization in animal models of Alzheimer’s disease17.”
From Tau co-organizes dynamic microtubule and actin networks (2015) · cites this paper as [17]
Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity.
“Tau phosphorylation at GSK3-target sites, as well as Ser262/356, has prominent effects on tau toxicity [26, 53–56].”
Studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity depends on tau phosphorylation at these sites.
“Notably, studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity caused by Aβ depends on tau phosphorylation at these sites [39, 45, 56–58].”
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- Authors
- Fulga, T. A., Elson-Schwab, I., Khurana, V., Steinhilb, M. L., Spires, T. L., Hyman, B. T., & Feany, M. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Fulga, Tudor A.
- Venue
- Nature Cell Biology
- Published
- 2006-12-24
- Volume
- 9
- Issue
- 2
- Pages
- 139-148
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2068011527
- Cited by
- 452
- References
- 6
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 10 · 2023: 23 · 2022: 24 · 2021: 28 · 2020: 26 · 2019: 23 · 2018: 20 · 2017: 26 · 2016: 25 · 2015: 21 · 2014: 26 · 2013: 23 · 2012: 27
- FWCI
- 14.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McKnight Foundation
- Massachusetts General Hospital
- John Douglas French Alzheimer's Foundation
- National Institutes of Health
- National Institute on Aging (AG-19790, P50AG005134, AG5134, R01AG019790)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau hyperphosphorylation, tauopathy, Alzheimer's disease, F-actin, actin cytoskeleton, neurodegeneration, amyloid-beta, Drosophila model, mouse model
- MeSH terms
- Actins, Alzheimer Disease, Animals, Cytoskeleton, Disease Models, Animal, Drosophila, Humans, Immunohistochemistry, Nerve Degeneration, Neurons, Phenotype, Amyloid beta-Peptides, tau Proteins, Mice
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