Propagation of Tau aggregates and neurodegeneration
Open accessAbstract
A pathway from the natively unfolded microtubule-associated protein Tau to a highly structured amyloid fibril underlies human Tauopathies. This ordered assembly causes disease and represents the gain of toxic function. In recent years, evidence has accumulated to suggest that Tau inclusions form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of pathology is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighboring cells. In mice, the intracerebral injection of Tau inclusions induces the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Conformational differences between Tau aggregates from transgenic mouse brain and in vitro assembled recombinant protein account for the greater seeding potency of brain aggregates. Short fibrils constitute the major species of seed-competent Tau in the brains of transgenic mice. The existence of multiple human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist.
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Pathological tau disrupts synaptic integrity and neuronal connectivity, driving neurodegeneration and cognitive decline.
“Pathological tau, characterized by hyperphosphorylation and aggregation into neurofibrillary tangles, disrupts synaptic integrity and neuronal connectivity, driving neurodegeneration and cognitive decline.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [14]
The Introduction (page not provided) identifies tau dysfunction as a cause of neurodegeneration, and Tau Toxicity reports synaptic-protein missorting and nerve-cell dysfunction in a mouse model. But Propagation of Tau Aggregates describes synaptic contacts and neuronal connectivity as routes for tau spread, not as structures that tau disrupts. The cited passages also do not establish the proposed chain from disrupted connectivity to cognitive decline. (LLM, conf=0.84)
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- Authors
- Goedert, M., Eisenberg, D. S., & Crowther, R. A.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Howard Hughes Medical Institute (US)
- Venue
- Annual Review of Neuroscience
- Publisher
- Annual Reviews
- Published
- 2017-07-25
- Volume
- 40
- Issue
- 1
- Pages
- 189-210
- ISSN
- 0147-006X (ISSN-L)
- 1545-4126
- OpenAlex
- W2618553145
- Cited by
- 632
- References
- 27
- Citations by year
- 2026: 44 · 2025: 71 · 2024: 63 · 2023: 98 · 2022: 69 · 2021: 94 · 2020: 87 · 2019: 48 · 2018: 49 · 2017: 9
- FWCI
- 6.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Cambridge
- European Commission
- National Institutes of Health (MC_U105184291)
- Medical Research Council (MC-U105184291)
- National Institute on Aging (R01AG029430, RF1AG054022)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, tauopathy, tau aggregates, amyloid fibrils, prion-like propagation, neurodegeneration, conformational strain, fibril morphology, transgenic mouse model, intrinsically disordered proteins, gain of toxic function
- MeSH terms
- Animals, Brain, Disease Models, Animal, Humans, Nerve Degeneration, Phosphorylation, Neurofibrillary Tangles, tau Proteins, Tauopathies
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