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Spread of pathological tau proteins through communicating neurons in human Alzheimer's disease
research-article
Author(s):
Jacob W. Vogel
1
,
,
Yasser Iturria-Medina
1 ,
Olof T. Strandberg
2 ,
Ruben Smith
2
,
3 ,
Elizabeth Levitis
1 ,
Alan C. Evans
1 ,
Oskar Hansson
2
,
3
,
,
Alzheimer’s Disease Neuroimaging Initiative,
the Swedish BioFinder Study
Publication date (Electronic):
26 May 2020
Journal:
Nature Communications
Publisher:
Nature Publishing Group UK
Read this article at
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Abstract
Tau is a hallmark pathology of Alzheimer’s disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (A β). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer’s disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain A β is present, but regions with greater A β burden show greater tau than predicted by connectivity patterns, suggesting a role of A β in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain A β.
Abstract
The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid
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Most cited references36
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- Abstract: found
- Article: not found
Primary age-related tauopathy (PART): a common pathology associated with human aging.
John F Crary, John Q Trojanowski, Julie A Schneider … (2014)
We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
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- Abstract: found
- Article: not found
Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease.
Alexandre Bejanin, Daniel Schonhaut, Renaud La Joie … (2017)
Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged-although less spatially extended-when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.
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- Article: not found
Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation
Ronald Gathagan, Virginia M-Y Lee, John Trojanowski … (2017)
Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque-associated tau pathogenesis.
Author and article information
Contributors
Jacob W. Vogel: jacob.vogel@mail.mcgill.ca
Oskar Hansson:
ORCID: http://orcid.org/0000-0001-8467-7286
oskar.hansson@med.lu.se
Journal
Journal ID (nlm-ta): Nat Commun
Journal ID (iso-abbrev): Nat Commun
Title:
Nature Communications
Publisher:
Nature Publishing Group UK
(London
)
ISSN
(Electronic):
2041-1723
Publication date
(Electronic):
26
May
2020
Publication date PMC-release: 26
May
2020
Publication date Collection: 2020
Volume: 11
Electronic Location Identifier: 2612
Affiliations
[1
]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Montreal Neurological Institute, , McGill University, ; Montréal, QC Canada
[2
]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Clinical Memory Research Unit, , Lund University, ; Lund, Sweden
[3
]ISNI 0000 0004 0623 9987, GRID grid.411843.b, Memory Clinic, , Skåne University Hospital, ; Lund, Sweden
[11
]ISNI 000000041936754X, GRID grid.38142.3c, Brigham and Women’s Hospital, , Harvard Medical School, ; Boston, MA USA
[13
]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Washington University St. Louis, ; St. Louis, MO USA
[14
]ISNI 0000 0004 1936 8972, GRID grid.25879.31, University of Pennsylvania, ; Philadelphia, PA USA
[26
]Khachaturian, Radebaugh & Associates, Inc and Alzheimer’s Association’s Ronald and
Nancy Reagan’s Research Institute, Chicago, IL USA
[29
]ISNI 0000 0000 9372 4913, GRID grid.419475.a, National Institute on Aging/National Institutes of Health, ; Bethesda, MD USA
[30
]ISNI 0000 0000 9758 5690, GRID grid.5288.7, Oregon Health and Science University, ; Portland, OR USA
[31
]ISNI 0000 0001 2156 6853, GRID grid.42505.36, University of Southern California, ; Los Angeles, CA USA
[32
]ISNI 0000 0001 2107 4242, GRID grid.266100.3, University of California San Diego, ; San Diego, CA USA
[34
]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Columbia University Medical Center, ; New York, NY USA
[36
]ISNI 0000000106344187, GRID grid.265892.2, University of Alabama Birmingham, ; Birmingham, MO USA
[37
]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Mount Sinai School of Medicine, ; New York, NY USA
[38
]ISNI 0000 0001 0705 3621, GRID grid.240684.c, Rush University Medical Center, ; Chicago, IL USA
[43
]ISNI 0000 0004 1936 8438, GRID grid.266539.d, University of Kentucky, ; city of Lexington, NC USA
[44
]ISNI 0000 0004 1936 9166, GRID grid.412750.5, University of Rochester Medical Center, ; Rochester, NY USA
[46
]ISNI 0000 0000 9482 7121, GRID grid.267313.2, University of Texas Southwestern Medical School, ; Dallas, TX USA
[48
]ISNI 0000 0001 2177 6375, GRID grid.412016.0, University of Kansas, Medical Center, ; Lawrence, KS USA
[51
]ISNI 0000000419368710, GRID grid.47100.32, Yale University School of Medicine, ; New Haven, CT USA
[56
]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Cleveland Clinic Lou Ruvo Center for Brain Health, ; Las Vegas, NV USA
[59
]ISNI 0000 0001 2186 0438, GRID grid.411667.3, Georgetown University Medical Center, ; Washington, DC USA
[62
]ISNI 0000 0004 0619 8759, GRID grid.414208.b, Banner Sun Health Research Institute, ; Sun City, AZ USA
[65
]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Case Western Reserve University, ; Cleveland, OH USA
[70
]ISNI 0000 0001 0668 7243, GRID grid.266093.8, University of California, Irvine BIC, ; Irvine, CA USA
[74
]ISNI 0000 0001 0626 2712, GRID grid.277313.3, Hartford Hosp, Olin Neuropsychiatry Research Center, ; Hartford, CT USA
[75
]ISNI 0000 0004 0440 749X, GRID grid.413480.a, Dartmouth Hitchcock Medical Center, ; Albany, NY USA
[76
]ISNI 0000 0004 0459 1231, GRID grid.412860.9, Wake Forest University Health Sciences, ; Winston-Salem, NC USA
[79
]ISNI 0000 0001 2189 3475, GRID grid.259828.c, Medical University South Carolina, ; Charleston, SC USA
[82
]ISNI 0000 0004 1936 8294, GRID grid.214572.7, University of Iowa College of Medicine, ; Iowa City, IA USA
[84
]ISNI 0000 0001 2353 285X, GRID grid.170693.a, University of South Florida, USF Health Byrd Alzheimer’s Institute, ; Tampa, FL 33613 USA
[86
]ISNI 0000 0004 0623 9987, GRID grid.411843.b, Department of Neurology, , Skåne University Hospital, ; Skåne, Sweden
[87
]ISNI 0000 0004 0623 9987, GRID grid.411843.b, Department of Neurosurgery, , Skåne University Hospital, ; Skåne, Sweden
Author information
Yasser Iturria-Medina
http://orcid.org/0000-0002-9345-0347
Ruben Smith
http://orcid.org/0000-0001-7147-0112
Oskar Hansson
http://orcid.org/0000-0001-8467-7286
Article
Publisher ID: 15701DOI: 10.1038/s41467-020-15701-2
PMC ID: 7251068
PubMed ID: 32457389
SO-VID: 335047e8-888b-4710-8a6f-5baa587c7e98
Copyright © © The Author(s) 2020
License:
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
History
Date
received
: 22
May
2019
Date
accepted
: 6
March
2020
Funding
Funded by: FundRef https://doi.org/10.13039/100011199, EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC
- Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the
European Community for Research, Technological Development and Demonstration Activities
(2007 to 2013));
Funded by: FundRef https://doi.org/10.13039/501100006636, Forskningsrådet om Hälsa, Arbetsliv och Välfärd (Swedish Research Council for Health,
Working Life and Welfare);
Funded by: FundRef https://doi.org/10.13039/501100004063, Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation);
Funded by: FundRef https://doi.org/10.13039/501100003252, Lunds Universitet (Lund University);
Funded by: FundRef https://doi.org/10.13039/501100003792, Hjärnfonden (Swedish Brain Foundation);
Funded by: FundRef https://doi.org/10.13039/100008444, Swedish Parkinson's Disease Association | Parkinsonfonden (Parkinson Foundation);
Funded by: FundRef https://doi.org/10.13039/100004032, Parkinson Research Foundation (PRF);
Funded by: Marianne and Marcus Wallenberg Foundation Swedish Alzheimer's Foundation the Skåne
University Hospital Foundation
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