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Cited by 236Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease

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Pooler, Amy M, Polydoro, Manuela, Maury, Eduardo A, Nicholls, Samantha B, Reddy, Snigdha M, Wegmann, Susanne, William, Christopher, Saqran, Lubna, Cagsal-Getkin, Ozge, Pitstick, Rose, Beier, David R, Carlson, George A, Spires-Jones, Tara L, Hyman, Bradley T·2015·Acta Neuropathologica Communications
DOI 10.1186/s40478-015-0199-xPMC PMC4371800
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Abstract

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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Figures

Figure 1 Patterns of human tau protein and deposition of Aβ in transgenic mouse models of AD. (a) Low-magnification view of a 16-month-old rTgTauEC horizontal brain section labeled with DAPI. Regions of interest are outlined in white; layer II of the EC, the primary expression site for the P301L transgene, is highlighted in yellow (scale bar = 500 μm). (b) rTgTauEC x APP/PS1 mice express human tau protein, labeled with a human-specific tau antibody Tau13 (green), and have robust deposition of amyloid plaques (anti-Aβ antibody AW7, red) at 16 months of age. DAPI staining for cell bodies appears in blue. No human tau positive neurons are observed in control (neuropsin promotor only) or APP/PS1 mice, and there is no detectable deposition of amyloid plaques in control or rTgTauEC mice. Scale bar = 500 μm.
Figure 1 Patterns of human tau protein and deposition of Aβ in transgenic mouse models of AD. (a) Low-magnification view of a 16-month-old rTgTauEC horizontal brain section labeled with DAPI. Regions of interest are outlined in white; layer II of the EC, the primary expression site for the P301L transgene, is highlighted in yellow (scale bar = 500 μm). (b) rTgTauEC x APP/PS1 mice express human tau protein, labeled with a human-specific tau antibody Tau13 (green), and have robust deposition of amyloid plaques (anti-Aβ antibody AW7, red) at 16 months of age. DAPI staining for cell bodies appears in blue. No human tau positive neurons are observed in control (neuropsin promotor only) or APP/PS1 mice, and there is no detectable deposition of amyloid plaques in control or rTgTauEC mice. Scale bar = 500 μm.CC BY · PubMed Central
Figure 2 Propagation of tauopathy along neural circuits is exacerbated by amyloid pathology. Low magnification view of horizontal sections of 16 month old brains from (a) rTgTauEC and (i) rTgTauEC x APP/PS1 mice, labeled with a human-specific tau antibody Tau13 (green) and cell bodies stained with DAPI (blue; scale bar = 1 mm), reveal increased propagation of tauopathy in rTgTauEC x APP/PS1 mice compared with rTgTauEC mice. (b, j) Higher magnification of layers of the DG showing the middle molecular layer (MML) and granule cell layer (GC; scale bar = 50 μm); and (c, k) CA1 fields of the hippocampus (scale bar = 50 μm) show human-tau positive cells in brain regions synaptically connected to the EC. Note apparent degeneration of the MML of the DG in rTgTauEC x APP/PS1 mice. In rTgTauEC x APP/PS1 mice, but not rTgTauEC mice, human tau is observed in brain regions distal to the EC such as somatosensory cortex (e, m) and accessory olfactory areas (f , n; scale bars 100 μm). (d, l) Immunolabeling for Alz50 (red; scale bar 50 μm), a marker of abnormally folded tau, was evident in neurons in the GC layer of the DG and increased in rTgTauEC x APP/PS1 mice compared with rTgTauEC mice. Again, loss of Alz50-positive terminals in the MML was observed. (g, h) Quantification of human tau-positive neurons in the DG granule cells immunolabeled with Tau13 (rTgTauEC, N = 7; rTgTauEC x APP/PS1, N = 10) or Alz50 (rTgTauEC, N = 7; rTgTauEC x APP/PS1, N = 7) in 16-month-old animals. Significantly more neurons containing human tau were observed in rTgTauEC x APP/PS1 mice compared with rTgTauEC mice, indicating increased propagation in this group. (o, p) In 10-month-old mice, human tau propagation (Tau13) from the EC to the DG was observed only in rTgTauEC x APP/PS1 mice (rTgTauEC, N = 7; rTgTauEC x APP/PS1, N = 7). Values represent mean ± s.e.m; *P < 0.05.
Figure 2 Propagation of tauopathy along neural circuits is exacerbated by amyloid pathology. Low magnification view of horizontal sections of 16 month old brains from (a) rTgTauEC and (i) rTgTauEC x APP/PS1 mice, labeled with a human-specific tau antibody Tau13 (green) and cell bodies stained with DAPI (blue; scale bar = 1 mm), reveal increased propagation of tauopathy in rTgTauEC x APP/PS1 mice compared with rTgTauEC mice. (b, j) Higher magnification of layers of the DG showing the middle molecular layer (MML) and granule cell layer (GC; scale bar = 50 μm); and (c, k) CA1 fields of the hippocampus (scale bar = 50 μm) show human-tau positive cells in brain regions synaptically connected to the EC. Note apparent degeneration of the MML of the DG in rTgTauEC x APP/PS1 mice. In rTgTauEC x APP/PS1 mice, but not rTgTauEC mice, human tau is observed in brain regions distal to the EC such as somatosensory cortex (e, m) and accessory olfactory areas (f , n; scale bars 100 μm). (d, l) Immunolabeling for Alz50 (red; scale bar 50 μm), a marker of abnormally folded tau, was evident in neurons in the GC layer of the DG and increased in rTgTauEC x APP/PS1 mice compared with rTgTauEC mice. Again, loss of Alz50-positive terminals in the MML was observed. (g, h) Quantification of human tau-positive neurons in the DG granule cells immunolabeled with Tau13 (rTgTauEC, N = 7; rTgTauEC x APP/PS1, N = 10) or Alz50 (rTgTauEC, N = 7; rTgTauEC x APP/PS1, N = 7) in 16-month-old animals. Significantly more neurons containing human tau were observed in rTgTauEC x APP/PS1 mice compared with rTgTauEC mice, indicating increased propagation in this group. (o, p) In 10-month-old mice, human tau propagation (Tau13) from the EC to the DG was observed only in rTgTauEC x APP/PS1 mice (rTgTauEC, N = 7; rTgTauEC x APP/PS1, N = 7). Values represent mean ± s.e.m; *P < 0.05.CC BY · PubMed Central
Figure 3 Tauopathy-induced neurodegeneration is enhanced by amyloid deposition. (a) Histochemistry of AChE fibers in the DG shows deafferentation-induced reorganization in the MML in 16-month-old rTgTauEC x APP/PS1 mice. Increased AChE staining in the MML is indicated by the arrow. (b) Comparing the ratio of optical densities between MML and IML demonstrates that the sprouting of AChE fibers is significant at 16 months of age in rTgTauEC x APP/PS1 mice compared to rTgTauEC, but no synaptic reorganization is evident in 10-month-old animals (10 and 16 month old animals, N = 3). (c, d) High magnification views of the EC with FISH showing human tau mRNA (green) and immunostained for human tau protein (Tau13, red; scale bar = 50 μm). Transgene expression was robust in layer II of the EC in rTgTauEC mice, but nearly absent in rTgTauEC x APP/PS1 mice, despite strong labeling for human tau protein. (e) (Left) Quantification of FISH labeling reveals that rTgTauEC x APP/PS1 mice have a significant reduction in transgene expressing cells in the EC compared with rTgTauEC mice (rTgTauEC, N = 3; rTgTauEC x APP/PS1, N = 6). (Right) The EC of rTgTauEC x APP/PS1 mice also contained fewer cells that were positive for both human tau mRNA and tau protein. (f) Layer II of the EC of rTgTauEC x APP/PS1 mice contained significantly fewer cells than rTgTauEC mice. Values represent mean ± s.e.m; *P < 0.05, ***P < 0.001.
Figure 3 Tauopathy-induced neurodegeneration is enhanced by amyloid deposition. (a) Histochemistry of AChE fibers in the DG shows deafferentation-induced reorganization in the MML in 16-month-old rTgTauEC x APP/PS1 mice. Increased AChE staining in the MML is indicated by the arrow. (b) Comparing the ratio of optical densities between MML and IML demonstrates that the sprouting of AChE fibers is significant at 16 months of age in rTgTauEC x APP/PS1 mice compared to rTgTauEC, but no synaptic reorganization is evident in 10-month-old animals (10 and 16 month old animals, N = 3). (c, d) High magnification views of the EC with FISH showing human tau mRNA (green) and immunostained for human tau protein (Tau13, red; scale bar = 50 μm). Transgene expression was robust in layer II of the EC in rTgTauEC mice, but nearly absent in rTgTauEC x APP/PS1 mice, despite strong labeling for human tau protein. (e) (Left) Quantification of FISH labeling reveals that rTgTauEC x APP/PS1 mice have a significant reduction in transgene expressing cells in the EC compared with rTgTauEC mice (rTgTauEC, N = 3; rTgTauEC x APP/PS1, N = 6). (Right) The EC of rTgTauEC x APP/PS1 mice also contained fewer cells that were positive for both human tau mRNA and tau protein. (f) Layer II of the EC of rTgTauEC x APP/PS1 mice contained significantly fewer cells than rTgTauEC mice. Values represent mean ± s.e.m; *P < 0.05, ***P < 0.001.CC BY · PubMed Central
Figure 4 The presence of human tau exacerbates amyloid plaque-induced axonal dystrophy. (a) Amyloid plaques in the MML were visualized with the antibody AW7, and were co-immunostained with SMI312, an axonal marker, and with the tau-specific Alz50 antibody (scale bar = 50 μm). Dystrophic axonal puncta are indicated by white arrows. (b) Quantification of SMI312-positive puncta within amyloid plaques revealed significantly more dystrophic axons in rTgTauEC x APP/PS1 mice compared with APP/PS1 mice. Further analysis of individual amyloid plaques showed a significant correlation between the numbers Alz50-positive and SMI312 axonal puncta (APP/PS1, N = 4; rTgTauEC x APP/PS1, N = 5). Values represent mean ± s.e.m; *P < 0.05.
Figure 4 The presence of human tau exacerbates amyloid plaque-induced axonal dystrophy. (a) Amyloid plaques in the MML were visualized with the antibody AW7, and were co-immunostained with SMI312, an axonal marker, and with the tau-specific Alz50 antibody (scale bar = 50 μm). Dystrophic axonal puncta are indicated by white arrows. (b) Quantification of SMI312-positive puncta within amyloid plaques revealed significantly more dystrophic axons in rTgTauEC x APP/PS1 mice compared with APP/PS1 mice. Further analysis of individual amyloid plaques showed a significant correlation between the numbers Alz50-positive and SMI312 axonal puncta (APP/PS1, N = 4; rTgTauEC x APP/PS1, N = 5). Values represent mean ± s.e.m; *P < 0.05.CC BY · PubMed Central
Figure 5 Expression of human tau increases amyloid plaque burden. (a) Low-magnification view of horizontal brain sections from APP/PS1 and rTgTauEC x APP/PS1 mice at 10 months of age (Top) and APP/PS1, rTgTauEC x APP/PS1 and control mice at 16 months of age (Bottom), immunostained with AW7 antibody to visualize amyloid plaques. Regions of interest are outlined in white on control (neuropsin promotor only) image (scale bar = 1 mm). (b) Top: Quantification of amyloid plaque area revealed significantly larger plaques in rTgTauEC x APP/PS1 mice compared with APP/PS1 mice the EC in 10- and 16 months of age, and in the somatosensory cortex at 16 months of age. Bottom: The number of amyloid plaques was also increased in 16-month-old rTgTauEC x APP/PS1 mice in both the EC and somatosensory cortices (10 months: APP/PS1, N = 7; rTgTauEC x APP/PS1, N = 7. 16 months: APP/PS1, N = 4; rTgTauEC x APP/PS1, N = 11). (c) Expression of human APP transgene was assessed by qPCR. No differences in APP mRNA were observed in 16-month-old APP/PS1 vs. rTgTauEC x APP/PS1 mice (APP/PS1, N = 3; rTgTauEC x APP/PS1, N = 5). Values represent mean ± s.e.m; *P < 0.05, **P < 0.01, ***P < 0.001.
Figure 5 Expression of human tau increases amyloid plaque burden. (a) Low-magnification view of horizontal brain sections from APP/PS1 and rTgTauEC x APP/PS1 mice at 10 months of age (Top) and APP/PS1, rTgTauEC x APP/PS1 and control mice at 16 months of age (Bottom), immunostained with AW7 antibody to visualize amyloid plaques. Regions of interest are outlined in white on control (neuropsin promotor only) image (scale bar = 1 mm). (b) Top: Quantification of amyloid plaque area revealed significantly larger plaques in rTgTauEC x APP/PS1 mice compared with APP/PS1 mice the EC in 10- and 16 months of age, and in the somatosensory cortex at 16 months of age. Bottom: The number of amyloid plaques was also increased in 16-month-old rTgTauEC x APP/PS1 mice in both the EC and somatosensory cortices (10 months: APP/PS1, N = 7; rTgTauEC x APP/PS1, N = 7. 16 months: APP/PS1, N = 4; rTgTauEC x APP/PS1, N = 11). (c) Expression of human APP transgene was assessed by qPCR. No differences in APP mRNA were observed in 16-month-old APP/PS1 vs. rTgTauEC x APP/PS1 mice (APP/PS1, N = 3; rTgTauEC x APP/PS1, N = 5). Values represent mean ± s.e.m; *P < 0.05, **P < 0.01, ***P < 0.001.CC BY · PubMed Central

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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
Publisher
Springer Science and Business Media LLC
Published
2015-03-24
Volume
3
Issue
1
Pages
14-14
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-015-0199-x
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
Licence
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
  • 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, 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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