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Mechanisms of Cell-to-Cell Transmission of Pathological Tau: A Review

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Gibbons, Garrett S., Lee, Virginia M. Y., Trojanowski, John Q.·2019·JAMA Neurology
DOI 10.1001/jamaneurol.2018.2505PMC PMC6382549
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Abstract

Importance: Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease. Emerging evidence supports a model of cell-to-cell transmission of proteinaceous pathological tau seeds, which leads to recruitment and templated fibrillization of endogenous cellular tau followed by the spread of abnormal tau throughout the brain. These findings lead to the strain hypothesis, which predicts that distinct conformational strains or polymorphs of tau may underlie the clinical and neuropathological heterogeneity and cell-type specificity of tauopathies. In this review, we describe the evidence for propagation of distinct tau strains in cell culture and animal models of AD and mechanistic insights into cell-to-cell transmission of pathological tau. Observations: Intracranial injections of synthetic tau-preformed fibrils and human brain-derived pathological tau into nontransgenic wild-type mice and transgenic mouse models of AD expressing β-amyloid and tau-amyloid deposits yield widespread pathological tau aggregates observed in neuroanatomically connected brain regions distant from the site of injection. Furthermore, when human brain-derived pathological tau obtained from distinct tauopathies (ie, brains with AD, PSP, and CBD) were injected into the brains of wild-type mice, they seeded tau pathology and faithfully recapitulated cell-type specific tau inclusions characteristic of each tauopathy in a time-dependent, dose-dependent, and injection site-dependent spread reflective of the connectome of the injection site. Conclusions and Relevance: These findings provide compelling evidence that misfolded or pathological conformers of tau undergo cell-to-cell spread in a tauopathy strain-specific manner. Importantly, evidence to date supports that pathological tau strains do not behave like infectious agents, despite growing evidence that these tau strains undergo templated propagation and spread linked to the neuroanatomical connectome of the injection site.

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  • There was an interaction between clusters 1 and 3 that captures the accumulation and colocalization of pTDP-43 inclusions in pTau-bearing cells, as described previously.

    “Furthermore, we observed an interaction between clusters 1 and 3 (Fig. 2c, blue box and Extended Data Fig. 4d) that captures the accumulation and colocalization of pTDP-43 inclusions in pTau-bearing cells, as described previously46.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [46]

    The cited paper’s ‘AD Pathological Hallmarks and Spatiotemporal Spread’ section discusses tau inclusions and coincident proteinopathies, but does not describe pTDP-43 inclusions colocalizing with pTau in the same cells. Searches for TDP-43 colocalization and tau co-pathology found no passage addressing that point. The cluster interaction is presented as the citing authors’ own observation, not as a finding attributed to this source. (LLM, conf=0.76)

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  • These neurons are lost earlier than L2/3 IT excitatory types, which bear the highest Tau burden in the cortex, suggesting high pathological susceptibility and an initial event of circuit dysfunction.

    “These neurons are lost earlier than L2/3 IT excitatory types, which bear the highest Tau burden in the cortex46, suggesting high pathological susceptibility and an initial event of circuit dysfunction.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [46]

    The citation is attached to the assertion that L2/3 IT excitatory neurons bear the highest cortical tau burden. The ‘AD Pathological Hallmarks and Spatiotemporal Spread’ section describes regional progression of tau pathology, but the passages found do not compare tau burden across cortical neuron types. Searches for L2/3 IT neurons and cortical tau burden found no passage addressing that comparison; page numbers were not available in our copy. (LLM, conf=0.74)

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Cited by

Sorted by citations

Authors
Gibbons, G. S., Lee, V. M. Y., & Trojanowski, J. Q.
Affiliations
University of Pennsylvania (US)
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2019-01-01
Volume
76
Issue
1
Pages
101
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2018.2505
PMC
PMC6382549
OpenAlex
W2892135048
Cited by
257
References
18
Citations by year
2026: 25 · 2025: 40 · 2024: 37 · 2023: 28 · 2022: 35 · 2021: 39 · 2020: 31 · 2019: 19 · 2018: 3
FWCI
3.02
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (F32AG053036, P30AG010124, P01AG017586)
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 › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
pathological tau, cell-to-cell transmission, tauopathy, Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, transgenic mouse model, tau propagation
MeSH terms
Animals, Brain, Cell Communication, Humans, tau Proteins, Protein Folding, Tauopathies

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