Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease
Open accessAbstract
INTRODUCTION: In early stages of Alzheimer's disease (AD), neurofibrillary tangles (NFT) are largely restricted to the entorhinal cortex and medial temporal lobe. At later stages, when clinical symptoms generally occur, NFT involve widespread limbic and association cortices. At this point in the disease, amyloid plaques are also abundantly distributed in the cortex. This observation from human neuropathological studies led us to pose two alternative hypotheses: that amyloid in the cortex is permissive for the spread of tangles from the medial temporal lobe, or that these are co-occurring but not causally related events simply reflecting progression of AD pathology. RESULTS: We now directly test the hypothesis that cortical amyloid acts as an accelerant for spreading of tangles beyond the medial temporal lobe. We crossed rTgTauEC transgenic mice that demonstrate spread of tau from entorhinal cortex to other brain structures at advanced age with APP/PS1 mice, and examined mice with either NFTs, amyloid pathology, or both. We show that concurrent amyloid deposition in the cortex 1) leads to a dramatic increase in the speed of tau propagation and an extraordinary increase in the spread of tau to distal brain regions, and 2) significantly increases tau-induced neuronal loss. CONCLUSIONS: These data strongly support the hypothesis that cortical amyloid accelerates the spread of tangles throughout the cortex and amplifies tangle-associated neural system failure in AD.
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Presence of cortical Aβ plaques accelerates the development of tauopathy along the perforant pathway and synergizes with tau-related neurodegeneration.
“Another study has shown that presence of cortical Aβ plaques accelerates the development of tauopathy along the perforant pathway and synergizes with tau-related neurodegeneration (6).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [6]
Prior studies showed that either co-expressing APP and MAPT genes or using prion-like seeding paradigms led to exacerbated Aβ and tau pathologies.
“Previous studies have shown that either co-expressing APP and MAPT genes (3, 6, 23) or using prion-like seeding paradigms (4, 24, 25) led to exacerbated Aβ and tau pathologies.”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [6]
Aβ plays a permissive role for the spread of tau pathology in vivo.
“Furthermore, Aβ plays a permissive role for the spread of tau pathology in vivo (Pooler et al., 2015).”
From Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice (2017) · cites this paper as Pooler et al., 2015
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- Authors
- Pooler, A. M., Polydoro, M., Maury, E. A., Nicholls, S. B., Reddy, S. M., Wegmann, S., William, C., Saqran, L., Cagsal-Getkin, O., Pitstick, R., Beier, D. R., Carlson, G. A., Spires-Jones, T. L., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- McLaughlin Research Institute (US)
- Seattle Children's Research Institute (US)
- Corresponding author
- Hyman, Bradley T
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2015-03-24
- Volume
- 3
- Issue
- 1
- Pages
- 14-14
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4371800
- OpenAlex
- W2107141858
- Cited by
- 236
- References
- 30
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 20 · 2023: 26 · 2022: 20 · 2021: 24 · 2020: 30 · 2019: 17 · 2018: 25 · 2017: 23 · 2016: 16 · 2015: 5
- FWCI
- 16.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (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)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association (ZEN-09-132524)
- American Health Assistance Foundation
- Glenn Foundation for Medical Research
- Alzheimer's Society
- National Institutes of Health
- National Institute on Aging (R01AG026249, 5T32AG00022222, R00AG033670, P50AG005134, R21AG03885, T32AG000222, P30AG062421)
- Topics
- Health Sciences › Medicine › Physiology › 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, amyloid plaques, tau propagation, neurofibrillary tangles, tauopathy, cortical amyloid, entorhinal cortex, APP/PS1 mice, transgenic mouse model, neuronal loss, tau toxicity, disease progression
- MeSH terms
- Aging, Alzheimer Disease, Amyloid, Animals, Brain, Cerebral Cortex, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Neurons, Temporal Lobe, Neurofibrillary Tangles, tau Proteins, Disease Progression, Mice
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