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Cited by 286Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer’s Disease Brain

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DeVos, Sarah L., Corjuc, Bianca T., Oakley, Derek H., Nobuhara, Chloe K., Bannon, Riley N., Chase, Alison, Commins, Caitlin, Gonzalez, Jose A., Dooley, Patrick M., Frosch, Matthew P., Hyman, Bradley T.·2018·Frontiers in Neuroscience
DOI 10.3389/fnins.2018.00267PMC PMC5928393
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Abstract

Alzheimer’s disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates and extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate to the progression of AD. Several in vitro and in vivo studies have examined tau pathology moving from one neuron to the next, suggesting a “prion-like” spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate – ie., tau aggregates that are capable of recruiting and misfolding monomeric tau – , we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human AD.

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Figures

Figure 1 Tau seeding activity can be found in brain regions with rare tau pathology. (A) Representative western blot for total tau and PHF-1 phospho-tau of the cerebellum (Cb), entorhinal cortex (EC), and primary visual cortex (V1) of Braak cases with rare NFTs in the EC (Low Braak; LB) and Braak cases with extensive NFTs across the brain (High Braak; HB). Dashed black line indicates discontinuous lanes on the blot. (B) Tau seeding as measured on the flow cytometer in the HEK239-TauRD-CFP/YFP seeding cells can be detected in the EC of Low Braak cases despite there being only rare tau pathology. (C) Representative photos of induced tau aggregates in the HEK239-TauRD-CFP/YFP cells. One-way ANOVA, Sidak post-hoc multiple comparisons. *p < 0.05, **p < 0.01. Individual dots represent individual human cases. Mean ± SEM.
Figure 1 Tau seeding activity can be found in brain regions with rare tau pathology. (A) Representative western blot for total tau and PHF-1 phospho-tau of the cerebellum (Cb), entorhinal cortex (EC), and primary visual cortex (V1) of Braak cases with rare NFTs in the EC (Low Braak; LB) and Braak cases with extensive NFTs across the brain (High Braak; HB). Dashed black line indicates discontinuous lanes on the blot. (B) Tau seeding as measured on the flow cytometer in the HEK239-TauRD-CFP/YFP seeding cells can be detected in the EC of Low Braak cases despite there being only rare tau pathology. (C) Representative photos of induced tau aggregates in the HEK239-TauRD-CFP/YFP cells. One-way ANOVA, Sidak post-hoc multiple comparisons. *p < 0.05, **p < 0.01. Individual dots represent individual human cases. Mean ± SEM.CC BY · PubMed Central
Figure 2 Tau Pathology along the Tau Braak Pathway. (A) Brain regions collected from human cases ranging from Braak I–Braak VI (Table 1). Each region corresponds to a region in the Braak Tau Pathway. They are as follows: Braak I, entorhinal cortex; Braak II, hippocampus; Braak III, posterior parahippocampal gyrus; Braak IV, anterior cingulate cortex; Braak V, visual association area; Braak VI, primary visual cortex. Additionally, the cerebellar vermis was collected as an unaffected control region. (B) Representative tau IHC photos of tau pathology in brain regions along the Braak Tau Pathway in different Braak staged cases. The Occipitotemporal Gyrus and Posterior Parahippocampal Gyrus can both be use for Braak III staging.
Figure 2 Tau Pathology along the Tau Braak Pathway. (A) Brain regions collected from human cases ranging from Braak I–Braak VI (Table 1). Each region corresponds to a region in the Braak Tau Pathway. They are as follows: Braak I, entorhinal cortex; Braak II, hippocampus; Braak III, posterior parahippocampal gyrus; Braak IV, anterior cingulate cortex; Braak V, visual association area; Braak VI, primary visual cortex. Additionally, the cerebellar vermis was collected as an unaffected control region. (B) Representative tau IHC photos of tau pathology in brain regions along the Braak Tau Pathway in different Braak staged cases. The Occipitotemporal Gyrus and Posterior Parahippocampal Gyrus can both be use for Braak III staging.CC BY · PubMed Central
Figure 3 Tau seeding activity precedes tau pathology along the Braak Tau Pathway. (A) Lysates along the Braak Tau Pathway for cases ranging from Braak I to Braak VI were all run on the tau seeding assay. Tau seeding values across the all brain regions analyzed were aggregated into a single value for each case and plotted against the Braak status of that brain. A significant direct correlation emerged, whereby as the Braak stage of the brain increases, so does the tau seeding activity across the whole brain. Spearman correlation. (B) Heatmap of tau seeding across the brain regions in the Braak Tau Pathway in human brains ranging from Braak I to Braak VI. Regions are organized left to right according to the progression of tau pathology throughout the course of AD; the EC is the first region to be impacted by tau pathology and the V1 is the last region. (C) Plots broken up based on the Braak stage of the brains. When compared to the unaffected cerebellum, tau seeding can be detected at least one region past where tau pathology is detected. Kruskal-Wallis test, Dunn's post-hoc multiple comparisons. #p < 0.01, *p < 0.05, **p < 0.01. Individual dots represent individual human cases. Mean ± SEM.
Figure 3 Tau seeding activity precedes tau pathology along the Braak Tau Pathway. (A) Lysates along the Braak Tau Pathway for cases ranging from Braak I to Braak VI were all run on the tau seeding assay. Tau seeding values across the all brain regions analyzed were aggregated into a single value for each case and plotted against the Braak status of that brain. A significant direct correlation emerged, whereby as the Braak stage of the brain increases, so does the tau seeding activity across the whole brain. Spearman correlation. (B) Heatmap of tau seeding across the brain regions in the Braak Tau Pathway in human brains ranging from Braak I to Braak VI. Regions are organized left to right according to the progression of tau pathology throughout the course of AD; the EC is the first region to be impacted by tau pathology and the V1 is the last region. (C) Plots broken up based on the Braak stage of the brains. When compared to the unaffected cerebellum, tau seeding can be detected at least one region past where tau pathology is detected. Kruskal-Wallis test, Dunn's post-hoc multiple comparisons. #p < 0.01, *p < 0.05, **p < 0.01. Individual dots represent individual human cases. Mean ± SEM.CC BY · PubMed Central
Figure 4 Tau seeding activity is found in axonally-rich brain regions with few to no neuronal cell bodies. (A) Representative western blot for pan-neuronal nuclei marker NeuN in optic nerve (ON), frontal cortex white matter (Fwhite), and frontal cortex gray matter (Fgray) from Braak V/VI human AD cases. Dashed black line indicates discontinuous lanes on the blot. (B) Western blot of total and PHF1 phospho-tau in Fwhite and Fgray matter samples, demonstrating that a small amount of phospho-tau exists in the Fwhite matter, despite there being almost no neuronal cell bodies. (C,D) Tau seeding is detected in both the Fgray lysates (C) and corresponding Fwhite lysates (D). The Fgray and Fwhite matter samples were run at the same time on the seeding assay. (E) Western Blot of total and PHF1 phospho-tau in control and Braak V/VI AD optic nerves. Phopsho-tau is more readily detected in AD optic nerves. (F) Tau seeding can be registered in optic nerve samples from AD human cases, despite there being no neuronal cell bodies. Two-tailed student's t-test. *p < 0.05, **p < 0.01. Individual dots represent individual human cases. Mean ± SEM.
Figure 4 Tau seeding activity is found in axonally-rich brain regions with few to no neuronal cell bodies. (A) Representative western blot for pan-neuronal nuclei marker NeuN in optic nerve (ON), frontal cortex white matter (Fwhite), and frontal cortex gray matter (Fgray) from Braak V/VI human AD cases. Dashed black line indicates discontinuous lanes on the blot. (B) Western blot of total and PHF1 phospho-tau in Fwhite and Fgray matter samples, demonstrating that a small amount of phospho-tau exists in the Fwhite matter, despite there being almost no neuronal cell bodies. (C,D) Tau seeding is detected in both the Fgray lysates (C) and corresponding Fwhite lysates (D). The Fgray and Fwhite matter samples were run at the same time on the seeding assay. (E) Western Blot of total and PHF1 phospho-tau in control and Braak V/VI AD optic nerves. Phopsho-tau is more readily detected in AD optic nerves. (F) Tau seeding can be registered in optic nerve samples from AD human cases, despite there being no neuronal cell bodies. Two-tailed student's t-test. *p < 0.05, **p < 0.01. Individual dots represent individual human cases. Mean ± SEM.CC BY · PubMed Central
Figure 5 Tau seeding activity is enriched in synapses along the Braak Tau Pathway. (A) Schematic of the Braak Tau Pathway. The cytosol and synaptosome fractions were isolated from the Hippocampus (Hp), Anterior Cingulate (AC), and Primary Visual cortex (V1) of human cases. Cases were broken up into early AD, Braak I–III—or late AD, Braak V–VI. The tau neurofibrillary tangle (NFT) burden for each brain region along the pathway shows not only a difference in how far tau pathology has reached, but also the NFT burden level—mild, moderate, or severe— in those regions. (B) Representative western blot showing the enrichment of PSD-95 (a synaptic protein) in the isolated synaptosome fraction compared to the cytosolic fraction. Actin was used as a loading control. (C) Cytosolic and synaptosome fractions from Braak I–III cases were run on western blot for total tau (left) and PHF1 phospho-tau. (D) All cytosolic and synaptosome fractions were run on the tau seeding assay and the cytosolic and synaptic tau seeding levels plotted across the Braak Tau Pathway for both the Braak I–III and Braak V–VI groups. The lines between the cytosolic and synaptic seeding values represent the same case. Two-way repeated measures ANOVA, Sidak post-hoc multiple comparisons. (E) The ratio of PHF1:Total tau on the western blot for all samples was plotted against the tau seeding levels of all the same samples, yielding a significant direct correlation. Overlaid is the line of best fit and the 95% confidence interval bands determined by linear regression. Spearman correlation. *p < 0.05, ****p < 0.0001. Individual dots represent individual human lysate samples.
Figure 5 Tau seeding activity is enriched in synapses along the Braak Tau Pathway. (A) Schematic of the Braak Tau Pathway. The cytosol and synaptosome fractions were isolated from the Hippocampus (Hp), Anterior Cingulate (AC), and Primary Visual cortex (V1) of human cases. Cases were broken up into early AD, Braak I–III—or late AD, Braak V–VI. The tau neurofibrillary tangle (NFT) burden for each brain region along the pathway shows not only a difference in how far tau pathology has reached, but also the NFT burden level—mild, moderate, or severe— in those regions. (B) Representative western blot showing the enrichment of PSD-95 (a synaptic protein) in the isolated synaptosome fraction compared to the cytosolic fraction. Actin was used as a loading control. (C) Cytosolic and synaptosome fractions from Braak I–III cases were run on western blot for total tau (left) and PHF1 phospho-tau. (D) All cytosolic and synaptosome fractions were run on the tau seeding assay and the cytosolic and synaptic tau seeding levels plotted across the Braak Tau Pathway for both the Braak I–III and Braak V–VI groups. The lines between the cytosolic and synaptic seeding values represent the same case. Two-way repeated measures ANOVA, Sidak post-hoc multiple comparisons. (E) The ratio of PHF1:Total tau on the western blot for all samples was plotted against the tau seeding levels of all the same samples, yielding a significant direct correlation. Overlaid is the line of best fit and the 95% confidence interval bands determined by linear regression. Spearman correlation. *p < 0.05, ****p < 0.0001. Individual dots represent individual human lysate samples.CC BY · PubMed Central

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Authors
DeVos, S. L., Corjuc, B. T., Oakley, D. H., Nobuhara, C. K., Bannon, R. N., Chase, A., Commins, C., Gonzalez, J. A., Dooley, P. M., Frosch, M. P., & Hyman, B. T.
Affiliations
Harvard University (US)
Corresponding author
Hyman, Bradley T.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2018-04-24
Volume
12
Pages
267-267
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2018.00267
PMC
PMC5928393
OpenAlex
W2800998714
Cited by
285
References
63
Citations by year
2026: 13 · 2025: 28 · 2024: 47 · 2023: 41 · 2022: 34 · 2021: 50 · 2020: 36 · 2019: 23 · 2018: 11
FWCI
20.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AG000222, AG026249)
  • BrightFocus Foundation
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
Alzheimer's disease, tau seeding, tau pathology, neurofibrillary tangles, Braak staging, prion-like spread, transneuronal spread, entorhinal cortex, optic nerve, synaptosomes, tau phosphorylation, P301S tau, human brain

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