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. 2014 Jul;95(Pt 7):1612–1618. doi: 10.1099/vir.0.062083-0

Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys

Pedro Piccardo 1,✉, Juraj Cervenak 1, Ming Bu 1, Lindsay Miller 1, David M Asher 1
PMCID: PMC4059271  PMID: 24769839

Abstract

Proteins aggregate in several slowly progressive neurodegenerative diseases called ‘proteinopathies’. Studies with cell cultures and transgenic mice overexpressing mutated proteins suggested that aggregates of one protein induced misfolding and aggregation of other proteins as well – a possible common mechanism for some neurodegenerative diseases. However, most proteinopathies are ‘sporadic’, without gene mutation or overexpression. Thus, proteinopathies in WT animals genetically close to humans might be informative. Squirrel monkeys infected with the classical bovine spongiform encephalopathy agent developed an encephalopathy resembling variant Creutzfeldt–Jakob disease with accumulations not only of abnormal prion protein (PrPTSE), but also three other proteins: hyperphosphorylated tau (p-tau), α-synuclein and ubiquitin; β-amyloid protein (Aβ) did not accumulate. Severity of brain lesions correlated with spongiform degeneration. No amyloid was detected. These results suggested that PrPTSE enhanced formation of p-tau and aggregation of α-synuclein and ubiquitin, but not Aβ, providing a new experimental model for neurodegenerative diseases associated with complex proteinopathies.

Proteinaceous fibrillar deposits accumulate in the brain before the onset and during the progression of several common ageing-associated neurodegenerative diseases (Josephs et al., 2009; Vlad et al., 2012). Relationships between the pathological proteins and overt disease remain unclear. As most chronic neurodegenerative diseases progress over years or even decades, pathological aggregates of proteins might produce different effects at different stages (Ballatore et al., 2007; Kirby et al., 2010). Aggregates of specific proteins are used to define some common human neurodegenerative diseases: β-amyloid (Aβ) plaques with neurofribrillary tangles (NFTs) of hyperphosphorylated tau (p-tau) protein in Alzheimer’s disease (AD), and Lewy bodies of α-synuclein in Parkinson’s and other diseases. Aggregates of abnormal prion protein (PrPTSE) are a hallmark of transmissible spongiform encephalopathies (TSEs; prion diseases) (Prusiner, 1982; Vlad et al., 2012). More than one protein might interact, accelerating progression of disease, e.g. normal PrP (PrPC) is a high-affinity binding site for Aβ, suggesting that PrPC might feature in the pathogenesis of AD (Nygaard & Strittmatter, 2009; Fluharty et al., 2013; Forloni et al., 2013). Tau and α-synuclein each promote aggregation of the other (Giasson et al., 2003). Aβ seems to promote hyperphosphorylation of tau via downregulation of the insulin signalling pathway in the brain (Tokutake et al., 2012). Thus, interactions between endogenous proteins in the central nervous system (CNS), whilst complex and poorly understood, probably play some role in neurodegeneration. Transgenic mice and cell cultures expressing mutant proteins yielded interesting information about genetic neurodegenerative diseases. However, most neurodegenerative diseases of humans are sporadic, without mutations or overexpression of proteins (Balducci & Forloni, 2011; Gilley et al., 2011). Experimental models in WT animals genetically close to humans might help elucidate complex proteinopathies.

We reported previously that squirrel monkeys (SQs) infected with the classical bovine spongiform encephalopathy (BSE) agent (SQ-BSE) developed an encephalopathy resembling variant Creutzfeldt–Jakob disease (vCJD) in humans (Piccardo et al., 2011, 2012). Here, we describe a neuropathologic study using site- and phosphorylation-specific antibodies for topographical analysis of p-tau by immunohistochemistry (IHC) and correlations with pathological features in SQ-BSE. In addition, tissue sections were probed with antibodies to apolipoprotein-E (Apo-E), α-synuclein, ubiquitin and synaptophysin (Table 1). A polyclonal antibody to bovine glial fibrillary acidic protein (GFAP) was also used (Table 1). IHC was performed using previously described protocols (Piccardo et al., 2012). Immunoreactivity was scored semiquantitatively by a four-point scale modified from Fraser & Dickinson (1967). Selected brain sections were treated with thioflavin-s to detect amyloid. In addition, formalin-fixed tissues from spleen, liver and kidney were used for histopathologic and immunohistochemical studies. Tissue sections were probed with anti-PrP antibodies 3F4 and 6H4 (Table 1).

Table 1. Antibodies used in the characterization of SQ-BSE.

Antibody Immunogen or epitope Concentration or dilution Source
4D6 Recombinant human α-synuclein 0.50 µg ml−1 Abcam
OC Human fibrillar oligomers 1 : 1000 Millipore
Apo-E Human apolipoprotein E 10.00 µg ml−1 Abcam
4G8 Human Aβ; amino acids 17–24 3.33 µg ml−1 Covance (Signet)
GFAP Glial fibrillary acidic protein 6.00 µg ml−1 DAKO
6H4 Human PrP; amino acids 144–152 0.285 µg ml−1 Prionics
3F4 Human PrP; amino acids 109–112 0.57 µg ml−1 Prionics
SYP-1 Synaptophysin 1 1.00 µg ml−1 Synaptic Systems
AT8 Human tau protein Ser202/Thr205 0.25 µg ml−1 Millipore
AT100 Human tau protein Ser212/Thr214 0.25 µg ml−1 Thermo Scientific
AT180 Human tau protein Thr231 0.25 µg ml−1 Thermo Scientific
AT270 Human tau protein Thr181 0.10 µg ml−1 Thermo Scientific
RD3 Human tau 3-repeat isoform 1 : 2000 Millipore
RD4 Human tau 4-repeat isoform 1 : 2000 Millipore
Ubi-1 Ubiquitin 1 5.00 µg ml−1 Abcam
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Neuropathologic studies showed that PrPTSE, p-tau and α-synuclein were deposited mainly at the periphery of vacuoles in the neuropil, affecting the same regions that had spongiform degeneration. All sections probed with the various anti-tau antibodies showed a similar staining pattern. (Figs 1c, d, 2a, b and 3, Table 2). No p-tau or α-synuclein was detected in SQs without TSE. IHC in brain sections of SQ-BSE without primary antibody was non-reactive, indicating that staining of tau and α-synuclein was specific. All six SQ-BSEs showed more PrPTSE (diffuse synaptic-like, pericellular and coarse deposits without amyloid properties) than p-tau and α-synuclein, suggesting that dose-dependent toxicity triggered by PrPTSE led to neurodegeneration. (Figs 2d and 3). Interestingly, no samples from SQ-BSEs reacted with antibodies to 3-repeat tau (RD3); 4-repeat tau (RD4) showed only limited staining – most prominent in a SQ-BSE with shortest incubation period (29 months) and longest duration of illness (5 months). The frontal cortex, thalamus and hypothalamus showed the most severe spongiform degeneration and accumulations of aggregated proteins (Table 2). Similar, but less intense, deposits occurred in molecular, granular and Purkinje cell layers of the cerebellum and in the brainstem, co-localized with intense spongiform degeneration. Similar aggregates of p-tau and α-synuclein were seen to occur in many neurodegenerative and lipid storage diseases, such as Niemann–Pick (Bu et al., 2002). Protein accumulation was minimal or absent in hippocampus and temporal cortex (areas with little or no spongiform degeneration or PrPTSE accumulation). When present, spongiform degeneration in the hippocampus was restricted to an area of the stratum lacunosum-moleculare. p-Tau and α-synuclein deposits always occurred in the same areas of the hippocampus with spongiform degeneration and PrPTSE, suggesting a strong correlation.

Fig. 1.

Fig. 1.

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SQs inoculated with classical BSE (SQ-BSE) develop severe TSE. (a) Spongiform degeneration, (b) astrogliosis, (c) PrPTSE deposition and (d) ubiquitin. Immunopositivity in the frontal cortex of a SQ-BSE. (a) Haematoxylin and eosin; (b–d) immunostaining for GFAP, PrP (6H4) and ubiquitin (Ubi-1), respectively. Bars, 100 µm.

Fig. 2.

Fig. 2.

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Accumulation of p-tau protein in the cerebrum of SQ-BSE. Granular and rod-shaped tau in the frontal cortex of SQ-BSE. (a–d, f) Immunopositivity observed with anti-tau antibodies AT8, AT100, AT180 and AT270, and anti-4-repeat tau, RD4, respectively. (e) No immunopositivity was observed in tissue sections probed with anti-3-repeat tau, RD3. Bars, 100 µm.

Fig. 3.

Fig. 3.

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α-Synucleinopathy in the cerebrum of SQ-BSE. (a, c, d) Granular α-synuclein immunopositivity in the frontal cortex of SQ-BSE with severe spongiform degeneration. (b) No α-synuclein accumulation in tissue sections of the temporal cortex (area without spongiform degeneration or PrPTSE deposition) of the same animal shown in (a, c, d). (e) Fine granular and evenly distributed synaptophysin immunoreactivity in the temporal cortex (area without spongiform degeneration or PrPTSE deposition) of SQ-BSE. (f) Reduced and disorganized synaptophysin immunoreactivity in frontal cortex of SQ-BSE with severe TSE. Bars, 100 µm (a, b, e, f); 50 µm (c, d).

Table 2. Profile of protein aggregates in the cerebrum and cerebellum of SQ-BSE.

Intensity of spongiform degeneration or immunoreactivity was scored semiquantitavely by a four-point scale modified from Fraser & Dickinson (1967). sds are given in parentheses.

Neuropathologic phenotype Frontal cortex Temporal cortex Thalamus Hypothalamus Hippocampus Cerebellum Brainstem
Spongiform degeneration 3.00 (0.00) 0.08 (0.20) 2.60 (0.49) 2.42 (0.49) 1.33 (1.17) 1.16 (1.01) 1.59 (1.14)
PrP 3.00 (0.00) 0.25 (0.42) 2.90 (0.20) 2.33 (0.41) 1.33 (0.61) 1.53 (0.97) 1.42 (1.22)
AT8 3.00 (0.00) 0.25 (0.42) 2.90 (0.20) 1.92 (0.58) 1.30 (0.67) 1.38 (0.87) 1.50 (1.24)
AT100 3.00 (0.00) 0.25 (0.42) 2.83 (0.26) 1.91 (1.20) 1.10 (0.89) 1.69 (0.85) 1.43 (1.12)
AT180 3.00 (0.00) 0.33 (0.60) 2.58 (0.58) 1.75 (1.12) 1.10 (0.89) 1.50 (1.20) 1.23 (1.24)
AT270 2.83 (0.40) 0.08 (0.20) 2.75 (0.42) 1.91 (0.97) 0.80 (0.27) 0.75 (0.96) 0.82 (1.08)
RD3 0 0 0 0 0 0 0
RD4 0.50 (0.63) 0.17 (0.41) 0.50 (0.63) 0.33 (0.82) 0.50 (0.55) 0.50 (0.84) 0.43 (0.787)
GFAP 2.58 (0.20) 0.58 (0.20) 2.60 (0.49) 2.33 (0.52) 1.66 (0.52) 2.00 (1.00) 2.1 (0.99)
OC 0 0 0 0 0 0 0
4G8 0 0 0 0 0 0 0
Ubi-1 3.00 (0.00) 0.70 (0.27) 2.75 (0.5) 3.00 (0.00) 0.50 (0.00) 1.00 (0.00) 1.43 (1.16)
α-Synuclein 2.00 (0.00) 0 2.00 (0.00) 2.00 (0.00) 1.50 (0.00) 1.34 (1.11) 1 (1.04)
Apo-E 0 0 0 0 0 0 0
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Sparing of the temporal cortex was confirmed by the finding that synaptophysin (fine granular and evenly distributed) remained unaffected in this cortical area, but was reduced and moderately disorganized in areas with severe spongiform degeneration accompanied by complex protein aggregates (PrPTSE, p-tau, ubiquitin and α-synuclein) and severe gliosis. To explore whether p-tau and α-synuclein co-localized, we double-stained brain sections from one SQ-BSE; for controls, we probed adjacent brain sections without primary antibody and brain sections from a SQ without TSE. Punctate and rod-shaped p-tau (AT8-reactive) and α-synuclein deposits co-localized in areas with severe spongiform degeneration (Fig. 4).

Fig. 4.

Fig. 4.

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p-Tau and α-synuclein co-localized in brain of SQ-BSE. (a) Small punctate α-synuclein (black arrows), (b) large granular and rod-shaped p-tau (red arrow heads), and (c) co-localization of α-synuclein (black arrows) and p-tau (red arrow heads) in the frontal cortex of SQ-BSE and severe spongiform degeneration. Tau was detected with antibody AT8 and α-synuclein was detected with antibody 4D6. Double staining was performed using Vectastain Elite ABC Kit (Vector Laboratories). (d) No immunopositivity was observed in tissue sections probed with normal mouse serum. Bars, 50 µm.

We detected no fibrillar oligomers (with antibody OC, recognizing epitopes common to various amyloid fibrils) and no Aβ- or Apo-E in any brain region of any SQ-BSE apart from one with a single small Aβ plaque in the temporal cortex (Table 2). We did observe discrete isolated areas of OC-reactive and Aβ plaque-like structures in the frontal and temporal cortical neuropil of one control SQ (without TSE). Normal ageing monkeys develop Aβ amyloid deposits in the brain (Walker et al., 1990), so we suspect that, Aβ and fibrillar oligomers in the control were age-related. No PrP immunopositivity was detected in any of the peripheral organs analysed.

The SQ-BSE model offers an opportunity to investigate several important issues associated with neurodegeneration: (i) pathogenesis of protein misfolding diseases, (ii) ante-mortem diagnosis and (iii) therapy. In SQ-BSE, neurotoxicity may well depend on post-translational modifications of brain proteins before PrP amyloid, p-tau NFTs and intracellular α-synuclein inclusions form. In all six SQ-BSEs, protein aggregated into fine granular and rod-shaped deposits in the cerebrum, cerebellum and brainstem. Aβ and Apo-E did not accumulate; this is not surprising because p-tau, for example, also accumulates without Aβ in primary tauopathies (Ludolph et al., 2009). We observed no florid plaques – a typical although non-specific feature in brains of patients with vCJD and macaques with BSE (Lasmézas et al., 1996, 2001, 2005; Will et al., 1996; Shimizu et al., 1999), but not in brains of cows, felines and mice with BSE (Wells et al., 1987; Williams et al., 2007) – showing that the host determines some important neuropathologic features of a TSE.

In our model, the co-localization of several proteins involved in neurodegeneration suggests that misfolding of one protein (probably PrPTSE) induced post-translational changes of other proteins, p-tau and α-synuclein, consistent with a report that the N terminus and repeat regions of tau interact with the octapeptide-repeat region of PrP to form heterologous protein aggregates (Wang et al., 2008). Tau and α-synuclein are intrinsically unstructured brain proteins (Nath et al., 2012) – tau a microtubule-associated protein stabilizing axonal microtubules in axons and α-synuclein localizing in axonal terminals. Another study found that α-synuclein induced the formation of tau fibrils and both molecules synergistically affected polymerization of the other (Giasson et al., 2003). p-Tau and α-synuclein might co-localize due to synergistic aggregation following the formation of PrPTSE. The consistent presence of mixed protein aggregates in a TSE suggests a possible common pathological pathway to neurodegeneration: if several neurodegenerative diseases share it, that pathway might offer a therapeutic target. Many studies have characterized PrPTSE associated with infectivity, but few have elucidated how PrPTSE actually damages the CNS. Several forms of PrPTSE were recently proposed as possibly neurotoxic (Jeffrey et al., 2012; Zhou et al., 2012). Brains of SQ-BSEs contained neither fibrillar oligomers nor mature amyloid, implying that severe neurodegeneration more likely resulted from smaller non-fibrillar PrPTSE species. Whether there are different PrPTSE species, one associated with infectivity and another causing neurotoxicity, remains unknown.

All six SQ-BSEs developed a complex proteinopathy lacking important neuropathologic features common to several other human neurodegenerative diseases. For example, brains of patients with Gerstmann–Sträussler–Scheinker disease, particularly those with PrP mutations F198S and Q217R, consistently accumulate PrPTSE amyloid with p-tau (NFTs identical to those in AD). Neuropil of SQ-BSE contained grains of RD4 resembling those of argyrophilic grain disease (AGD) – a common neurodegenerative disease of old age (Ferrer et al., 2008). Whilst AGD mainly affects the limbic system, SQ-BSE preferentially affected the frontal cortex. SQ-BSE never shows p-tau deposits resembling those of progressive supranuclear palsy (Ince et al., 2008), astrocytic plaques of corticobasal degeneration (Togo et al. 2002; Lowe et al., 2008) or α-synuclein-staining Lewy bodies (Ghetti et al., 1989, 1996a, b; Tagliavini et al., 1993; Wittmann et al., 2001; Bautista et al., 2006; Ferrer et al., 2008; Giaccone et al., 2008; Jayadev et al., 2011; Reiniger et al., 2011). The tauopathy and α-synucleinopathy in SQ-BSE affected not only the cerebrum, but also the cerebellum – an area only recently recognized with tauopathy in TSEs and other neurodegenerative diseases (Giaccone et al., 2008; Furuoka et al., 2011; Reiniger et al., 2011; Sepulveda-Falla et al., 2011). In conclusion, the histopathology of SQ-BSE does not closely resemble those of human non-TSE neurodegenerative diseases.

Studies of cerebrospinal fluid (CSF) from patients with TSEs and other neurodegenerative diseases have sought molecular markers for ante-mortem diagnosis of dementias, especially the 14-3-3 group of proteins often increased in the CSF of patients with CJD, acute stroke, CNS infections and other inflammatory diseases, but less often in AD (Hsich et al., 1996; Zanusso et al., 2005; Bersano et al., 2006). A positive 14-3-3 protein assay, together with clinical features, sometimes aids in the differential diagnosis of sporadic CJD. Some dementing diseases were found to have typical profiles of several other proteins in the CSF (Green et al., 2010; Zanusso et al., 2011), e.g. elevated p-tau with Thr181 in the CSF of patients with vCJD (Goodall et al., 2006). p-Tau aggregates reacted strongly with antibody AT270, directed to p-tau Thr181, throughout the cerebrum and cerebellum of every SQ-BSE. The finding of elevated p-tau in vCJD CSF also suggests that abnormal tau might affect pathogenesis. Detecting abnormal tau might improve CSF tests for the differential diagnosis of neurodegenerative diseases (Zanusso et al., 2011; Green et al., 2010).

In conclusion, topographic analysis of the brains of six SQ-BSEs showed a close correlation between the degree of spongiform degeneration, PrPTSE, and deposits of p-tau, α-synuclein and ubiquitin, but not Aβ. Whether or not p-tau and α-synuclein contribute to progression of TSEs or result from brain damage remains to be determined. The complete absence of mature amyloid, in spite of severe proteinopathy, in all SQ-BSEs suggests that oligomeric aggregates of PrP and other proteins are probably the most pathogenic species.

Acknowledgements

We thank Drs Dagmar Heim (Federal Veterinary Office, Bern, Switzerland) and Torsten Seuberlich (NeuroCentre, National and OIE Reference Laboratories for BSE and Scrapie, Vetsuisse Faculty, University of Bern, Bern, Switzerland) for providing the BSE inoculum, and Steve Harbaugh and Jeff Harbaugh (Bioqual, Rockville, MD, USA) for dedicated care of animals. This work was funded by NIH-NIAID agreement no. Y1-AI-4893-02 with the Food and Drug Administration (FDA; agreement no. 224-05-1307): Potential of Candidate Cell Substrates for Vaccine Production to Propagate the Agents of Transmissible Spongiform Encephalopathies (Main Agreement Title: Assessing Safety of Cell Substrates and Vaccine Components). The findings and conclusions in this paper have not been formally disseminated by the FDA and should not be construed to represent any Agency determination or policy.

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