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Cited by 140Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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The aged rhesus macaque manifests Braak stage III/IV Alzheimer's‐like pathology

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Paspalas, Constantinos D., Carlyle, Becky C., Leslie, Shannon, Preuss, Todd M., Crimins, Johanna L., Huttner, Anita J., van Dyck, Christopher H., Rosene, Douglas L., Nairn, Angus C., Arnsten, Amy F.T.·2018·Alzheimer's & Dementia
DOI 10.1016/j.jalz.2017.11.005PMC PMC6178089
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Abstract

Introduction: An animal model of late‐onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration. Methods: We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays. Results: Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV. Pathology began in the young‐adult entorhinal cortex with protein kinase A‐phosphorylation of tau, progressing to fibrillation with paired helical filaments and mature tangles in oldest animals. Tau pathology in the dorsolateral prefrontal cortex paralleled but lagged behind the entorhinal cortex, not afflicting the primary visual cortex. Discussion: The aging rhesus macaque provides the long‐sought animal model for exploring the etiology of late‐onset Alzheimer's disease and for testing preventive strategies.

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Figures

Fig. 1. Tau phosphorylation in the layer II ERC of young-adult macaque (7–9 years). (A) Stellate cell islands (red ovals) react against pSer214-tau. (B) Correlated light/electron microscopy shows labeling in a principal dendrite (pseudocolored). (C and D) pSer214-tau-reactive microtubules (green-pseudocolored) in cross-sectioned (C) and longitudinally sectioned (D) dendrites; an endosome [cyan-pseudocolored in (D)] is “entrapped” along the microtubules by heavy aggregation of pSer214-tau. (E) Endo/exocytosis (frame and inset) of pSer214-tau; white arrowheads point to an omegashaped profile on the plasma membrane. The elaborate SER (see below) is pink-pseudocolored. (F and G) In ERC dendrites, both the synapse and DSR (i.e., Ca2+-storing SER expansion subjacent to glutamatergic-like synapses) accumulate pSer214-tau. (H and I) DSR cisterns but not the synapses react against pSer2808-RyR2 (yellow arrowheads). Red arrowheads point to pSer214-tau; synapses are between arrows. Scale bars, 30 μm (A), 500 nm (B), 50 nm (C,D), 200 nm (E–I). Abbreviations: Ax, axon; Den, dendrite; DSR, dendritic subsynaptic reticulum; ERC, entorhinal cortex; Mit, mitochondrion; pSer214-tau, protein kinase A-phosphorylated tau; SER, smooth endoplasmic reticulum.
Fig. 1. Tau phosphorylation in the layer II ERC of young-adult macaque (7–9 years). (A) Stellate cell islands (red ovals) react against pSer214-tau. (B) Correlated light/electron microscopy shows labeling in a principal dendrite (pseudocolored). (C and D) pSer214-tau-reactive microtubules (green-pseudocolored) in cross-sectioned (C) and longitudinally sectioned (D) dendrites; an endosome [cyan-pseudocolored in (D)] is “entrapped” along the microtubules by heavy aggregation of pSer214-tau. (E) Endo/exocytosis (frame and inset) of pSer214-tau; white arrowheads point to an omegashaped profile on the plasma membrane. The elaborate SER (see below) is pink-pseudocolored. (F and G) In ERC dendrites, both the synapse and DSR (i.e., Ca2+-storing SER expansion subjacent to glutamatergic-like synapses) accumulate pSer214-tau. (H and I) DSR cisterns but not the synapses react against pSer2808-RyR2 (yellow arrowheads). Red arrowheads point to pSer214-tau; synapses are between arrows. Scale bars, 30 μm (A), 500 nm (B), 50 nm (C,D), 200 nm (E–I). Abbreviations: Ax, axon; Den, dendrite; DSR, dendritic subsynaptic reticulum; ERC, entorhinal cortex; Mit, mitochondrion; pSer214-tau, protein kinase A-phosphorylated tau; SER, smooth endoplasmic reticulum.CC BY-NC-ND · PubMed Central
Fig. 2 . Tau fibrillation (AT8 labeling) in the aging macaque ERC. (A) Mild tau fibrillation is restricted in layer II cell islands (red ovals; 26 years). (B) Advanced fibrillation in layer II islands extends into the deeper ERC (33 years). (C and D) Mature NFTs in layer II (C) and layer V (D) ERCs (38 years). (E) Correlated light/electron microscopy reveals loose fibril bundles (red ovals) in the tapering proximal dendrite, consistent with NFTs (33 years). (F) Individual fibrils react against PHF-tau (red arrowheads). (G and H) High-power microscopy demonstrates 10-nm filament strands in a double-helix twist with a cross-over repeat of 80 nm (parallel bars), and with varying width of 10–22 nm (G), identical to PHFs in AD (H). (I) AT8-reactive PHFs (red arrowheads) end abruptly, exposing paired 10-nm filament strands (white arrowheads; 34 years). (J) Correlated light/electron microscopy of a pretangle layer II stellate neuron (34 years). Asterisks mark autophagic vacuoles with multilamellar bodies in the soma and principal dendrite (pseudocolored). (K) “Ghost” dendrite (Den) of the degenerating neuron shown in (J); the entire cytoplasm is lysed. Scale bars, 100 μm (A and B), 10 μm (C and D), 500 nm (E, J, and K), 100 nm (F), 40 nm (G–I). Abbreviations: AD, Alzheimer’s disease; ERC, entorhinal cortex; NFTs, neurofibrillary tangles; PHF, paired helical filament; pSer214-tau, protein kinase A-phosphorylated tau.
Fig. 2 . Tau fibrillation (AT8 labeling) in the aging macaque ERC. (A) Mild tau fibrillation is restricted in layer II cell islands (red ovals; 26 years). (B) Advanced fibrillation in layer II islands extends into the deeper ERC (33 years). (C and D) Mature NFTs in layer II (C) and layer V (D) ERCs (38 years). (E) Correlated light/electron microscopy reveals loose fibril bundles (red ovals) in the tapering proximal dendrite, consistent with NFTs (33 years). (F) Individual fibrils react against PHF-tau (red arrowheads). (G and H) High-power microscopy demonstrates 10-nm filament strands in a double-helix twist with a cross-over repeat of 80 nm (parallel bars), and with varying width of 10–22 nm (G), identical to PHFs in AD (H). (I) AT8-reactive PHFs (red arrowheads) end abruptly, exposing paired 10-nm filament strands (white arrowheads; 34 years). (J) Correlated light/electron microscopy of a pretangle layer II stellate neuron (34 years). Asterisks mark autophagic vacuoles with multilamellar bodies in the soma and principal dendrite (pseudocolored). (K) “Ghost” dendrite (Den) of the degenerating neuron shown in (J); the entire cytoplasm is lysed. Scale bars, 100 μm (A and B), 10 μm (C and D), 500 nm (E, J, and K), 100 nm (F), 40 nm (G–I). Abbreviations: AD, Alzheimer’s disease; ERC, entorhinal cortex; NFTs, neurofibrillary tangles; PHF, paired helical filament; pSer214-tau, protein kinase A-phosphorylated tau.CC BY-NC-ND · PubMed Central
Fig. 3. Neuronal degeneration in the layer II of the aged macaque ERC (33–34 years). (A) Microglia (Mgl) engulfs a degenerating cellular profile containing large argyrophilic masses (yellow arrowheads), numerous late-phase lysosomes (Ls), and lipofuscin inclusions (Lf). (B) Detail of an AT8-labeled (red arrowheads) pretangle neuron (pseudocolored) with an abnormal accumulation of late-phase lysosomes (Ls). (C) A senile plaque composed of AT8-reactive dystrophic neurites (red arrowheads); compare with the senile plaque labeled against Aβ in Fig. 5A. (D) A dystrophic myelinated axon (red frame) contains numerous autophagosomes and a large vacuole in place of the inner mesaxon (asterisk). A second myelinated axon of typical appearance (black frame) is shown for size comparison. Scale bars, 1 μm (A, B, and D) and 30 μm (C). Abbreviations: Aβ, amyloid β; Ax, axon; ERC, entorhinal cortex.
Fig. 3. Neuronal degeneration in the layer II of the aged macaque ERC (33–34 years). (A) Microglia (Mgl) engulfs a degenerating cellular profile containing large argyrophilic masses (yellow arrowheads), numerous late-phase lysosomes (Ls), and lipofuscin inclusions (Lf). (B) Detail of an AT8-labeled (red arrowheads) pretangle neuron (pseudocolored) with an abnormal accumulation of late-phase lysosomes (Ls). (C) A senile plaque composed of AT8-reactive dystrophic neurites (red arrowheads); compare with the senile plaque labeled against Aβ in Fig. 5A. (D) A dystrophic myelinated axon (red frame) contains numerous autophagosomes and a large vacuole in place of the inner mesaxon (asterisk). A second myelinated axon of typical appearance (black frame) is shown for size comparison. Scale bars, 1 μm (A, B, and D) and 30 μm (C). Abbreviations: Aβ, amyloid β; Ax, axon; ERC, entorhinal cortex.CC BY-NC-ND · PubMed Central
Fig. 4. The pattern and sequence of tau phosphorylation in the macaque dlPFC parallels but lags behind the ERC. (A) Layer III pyramidal neurons in the aged dlPFC (31 years) react against pSer214-tau. (B) In dendritic spines, pSer214-tau aggregates over the synapse (between arrows) and the spine apparatus (pink-pseudocolored). (C) Tau fibrillation, revealed with the AT8 antibody, is sporadic in the aged dlPFC (33 years). (D and E) AT8-reactive PHFs with 80-nm helix periodicity (parallel bars in D) and abrupt endings (white arrowheads in E) as PHFs in AD. Red arrowheads point to pSer214-tau (A and B) or PHF-tau (C—E). Scale bars, 20 μm (A and C), 200 nm (B), 80 nm (D), and 40 nm (E). (F and G) Immunoblotting of tau shows more advanced phosphorylation state in the ERC than dlPFC, reflected by both increased tau at higher molecular weights (F) and increasing insolubility, S3/S1 (G). Changes in solubility are not observed across a similar age range in the dlPFC. Total tau was normalized to total protein (Supplementary Figs. 6 and 7). Abbreviations: AD, Alzheimer’s disease; Ax, axon; dlPFC, dorsolateral prefrontal cortex; ERC, entorhinal cortex; NFTs, neurofibrillary tangles; PHF, paired helical filament; pSer214-tau, protein kinase A-phos-phorylated tau; Sp, spine.
Fig. 4. The pattern and sequence of tau phosphorylation in the macaque dlPFC parallels but lags behind the ERC. (A) Layer III pyramidal neurons in the aged dlPFC (31 years) react against pSer214-tau. (B) In dendritic spines, pSer214-tau aggregates over the synapse (between arrows) and the spine apparatus (pink-pseudocolored). (C) Tau fibrillation, revealed with the AT8 antibody, is sporadic in the aged dlPFC (33 years). (D and E) AT8-reactive PHFs with 80-nm helix periodicity (parallel bars in D) and abrupt endings (white arrowheads in E) as PHFs in AD. Red arrowheads point to pSer214-tau (A and B) or PHF-tau (C—E). Scale bars, 20 μm (A and C), 200 nm (B), 80 nm (D), and 40 nm (E). (F and G) Immunoblotting of tau shows more advanced phosphorylation state in the ERC than dlPFC, reflected by both increased tau at higher molecular weights (F) and increasing insolubility, S3/S1 (G). Changes in solubility are not observed across a similar age range in the dlPFC. Total tau was normalized to total protein (Supplementary Figs. 6 and 7). Abbreviations: AD, Alzheimer’s disease; Ax, axon; dlPFC, dorsolateral prefrontal cortex; ERC, entorhinal cortex; NFTs, neurofibrillary tangles; PHF, paired helical filament; pSer214-tau, protein kinase A-phos-phorylated tau; Sp, spine.CC BY-NC-ND · PubMed Central
Fig. 5. Amyloid pathology in the aged macaque ERC (33–34 years). (A) A senile plaque is labeled against Aβ. (B and C) The plaque forms extracellularly and contains cell debris and a fibrous core (green ovals); enlarged in (C) to show individual Aβ fibrils (green arrowheads). (D–F) Intracellular Aβ (green arrowheads) is captured in endosomes (cyan-pseudocolored) in axons and dendrites. Note the Aβ-loaded endosomes next to the axonal plasma membrane (traced for clarity) in (F) and the accumulation of Aβ in the widened intercellular space (yellow asterisk). (G) Fibrils (white arrowheads) labeled with AT8 against PHF-tau (red arrowheads) surround endosomes (cyan-pseudocolored). (H) An APP-transporting endosome (immunogold; light green arrowhead) is surrounded by fibrils (white arrowheads) and PHF-tau aggregates (immunoperoxidase; red arrowheads). Synapses are between arrows. Scale bars, 20 μm (A), 200 nm (B and D–H), 30 nm (C). Abbreviations: Aβ, amyloid β; APP, amyloid precursor protein; Ax, axon; Den, dendrite; ERC, entorhinal cortex; Mit, mitochondrion; Mvb, multivesicular body; PHF, paired helical filament.
Fig. 5. Amyloid pathology in the aged macaque ERC (33–34 years). (A) A senile plaque is labeled against Aβ. (B and C) The plaque forms extracellularly and contains cell debris and a fibrous core (green ovals); enlarged in (C) to show individual Aβ fibrils (green arrowheads). (D–F) Intracellular Aβ (green arrowheads) is captured in endosomes (cyan-pseudocolored) in axons and dendrites. Note the Aβ-loaded endosomes next to the axonal plasma membrane (traced for clarity) in (F) and the accumulation of Aβ in the widened intercellular space (yellow asterisk). (G) Fibrils (white arrowheads) labeled with AT8 against PHF-tau (red arrowheads) surround endosomes (cyan-pseudocolored). (H) An APP-transporting endosome (immunogold; light green arrowhead) is surrounded by fibrils (white arrowheads) and PHF-tau aggregates (immunoperoxidase; red arrowheads). Synapses are between arrows. Scale bars, 20 μm (A), 200 nm (B and D–H), 30 nm (C). Abbreviations: Aβ, amyloid β; APP, amyloid precursor protein; Ax, axon; Den, dendrite; ERC, entorhinal cortex; Mit, mitochondrion; Mvb, multivesicular body; PHF, paired helical filament.CC BY-NC-ND · PubMed Central
Fig. 6. APP trafficking visualized in situ in the aged macaque dlPFC (33–34 years). (A) Detail of the soma of a layer III pyramidal neuron showing APP in the trans-Golgi network. (B) APP, which is internalized into endosomes via clathrin-mediated endocytosis, is captured in a clathrin-coated pit (white arrowheads point to the clathrin lattice); the labeled C-terminus protrudes intracellularly. (C and D) APP-transporting endosomes (cyan-pseudocolored) in an axon terminal (C) and a preterminal, that is, intervaricose, axon (D). (E) High-power magnification of tubular endosomes (cyan-pseudocolored) labeled against APP; the gold-tagged C-terminus is on the cytoplasmic face. The endosome on the right is curved so that its middle portion is out of the section plane. This portion corresponds to the surface of the endosome and reacts with the AT8 antibody, which shows accumulation of PHF-tau (red arrowheads). This fortunate section plane captures the direct interaction of fibrillated tau aggregates with a single APP-transporting endosome. Scale bars, 100 nm (A–E). Abbreviations: APP, amyloid precursor protein; Ax, axon; dlPFC, dorsolateral prefrontal cortex; PHF, paired helical filament.
Fig. 6. APP trafficking visualized in situ in the aged macaque dlPFC (33–34 years). (A) Detail of the soma of a layer III pyramidal neuron showing APP in the trans-Golgi network. (B) APP, which is internalized into endosomes via clathrin-mediated endocytosis, is captured in a clathrin-coated pit (white arrowheads point to the clathrin lattice); the labeled C-terminus protrudes intracellularly. (C and D) APP-transporting endosomes (cyan-pseudocolored) in an axon terminal (C) and a preterminal, that is, intervaricose, axon (D). (E) High-power magnification of tubular endosomes (cyan-pseudocolored) labeled against APP; the gold-tagged C-terminus is on the cytoplasmic face. The endosome on the right is curved so that its middle portion is out of the section plane. This portion corresponds to the surface of the endosome and reacts with the AT8 antibody, which shows accumulation of PHF-tau (red arrowheads). This fortunate section plane captures the direct interaction of fibrillated tau aggregates with a single APP-transporting endosome. Scale bars, 100 nm (A–E). Abbreviations: APP, amyloid precursor protein; Ax, axon; dlPFC, dorsolateral prefrontal cortex; PHF, paired helical filament.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Paspalas, C. D., Carlyle, B. C., Leslie, S., Preuss, T. M., Crimins, J. L., Huttner, A. J., van Dyck, C. H., Rosene, D. L., Nairn, A. C., & Arnsten, A. F. T.
Affiliations
  • Yale University (US)
  • Emory University (US)
  • Department of Neuroscience Yale School of Medicine New Haven CT USA
  • Boston University (US)
Corresponding author
  • Paspalas, Constantinos D.
  • Arnsten, Amy F.T.
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2017-12-11
Volume
14
Issue
5
Pages
680-691
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1016/j.jalz.2017.11.005
PMC
PMC6178089
OpenAlex
W2772269246
Cited by
140
References
51
Citations by year
2026: 14 · 2025: 22 · 2024: 21 · 2023: 20 · 2022: 11 · 2021: 27 · 2020: 13 · 2019: 8 · 2018: 4
FWCI
5.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • National Institute on Aging
  • National Institutes of Health (DP1AG047744, P50‐AG047270, RO1 AG043640)
  • Yerkes National Primate Research Center, Emory University (OD P51OD11132)
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, rhesus monkeys
MeSH terms
Aging, Alzheimer Disease, Amyloid, Animals, Brain, Disease Models, Animal, Macaca mulatta, Phosphorylation, Microscopy, Immunoelectron, Neurofibrillary Tangles, tau Proteins, Prefrontal Cortex, Disease Progression, Entorhinal Cortex, Plaque, Amyloid

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