Early preclinical detection of prions in the skin of prion-infected animals

Wang, Zerui; Manca, Matteo; Foutz, Aaron; Camacho, Manuel V.; Raymond, Gregory J.; Race, Brent; Orrú, Christina D.; Yuan, Jing; Shen, Pingping; Li, Baiya; Lang, Yue; Dang, Johnny; Adornato, Alise; Williams, Katie; Maurer, Nicholas R.; Gambetti, Pierluigi; Xu, Bin; Surewicz, Witold K.; Petersen, Robert B.; Dong, Xiao‐Ping; Appleby, Brian S.; Caughey, Byron; Cui, Li; Kong, Qingzhong; Zou, Wen-Quan

doi:10.1038/s41467-018-08130-9

Cited by 47 publications

(60 citation statements)

References 42 publications

(59 reference statements)

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“…This is based on the fact that the mechanisms underlying cytokine release could be a crucial target for therapeutic approaches in the central nervous system (CNS) in prion diseases [25]. Several other studies examined very early time points in scrapie, but most of them used experimental models in rodents [26][27][28] or in sheep [29], with just a few of them having used the natural model of the disease [30][31][32]. To study natural field cases of scrapie is, in our opinion, essential, because they represent a more feasible source of knowledge than experimental models.…”

Section: Discussionmentioning

confidence: 99%

Neuroimmune Response in Natural Preclinical Scrapie after Dexamethasone Treatment

Guijarro

Garcés

Marín

et al. 2020

IJMS

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A recently published report on chronic dexamethasone treatment for natural scrapie supported the hypothesis of the potential failure of astroglia in the advanced stage of disease. Herein, we aimed to extend the aforementioned study on the effect of this anti-inflammatory therapy to the initial phase of scrapie, with the aim of elucidating the natural neuroinflammatory process occurring in this neurodegenerative disorder. The administration of this glucocorticoid resulted in an outstanding reduction in vacuolation and aberrant protein deposition (nearly null), and an increase in glial activation. Furthermore, evident suppression of IL-1R and IL-6 and the exacerbation of IL-1α, IL-2R, IL-10R and IFNγR were also demonstrated. Consequently, the early stage of the disease is characterized by an intact neuroglial response similar to that of healthy individuals attempting to re-establish homeostasis. A complex network of neuroinflammatory markers is involved from the very early stages of this prion disease, which probably becomes impaired in the more advanced stages. The in vivo animal model used herein provides essential observations on the pathogenesis of natural scrapie, as well as the possibility of establishing neuroglia as potential target cells for anti-inflammatory therapy.

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Section: Discussionmentioning

confidence: 99%

Neuroimmune Response in Natural Preclinical Scrapie after Dexamethasone Treatment

Guijarro

Garcés

Marín

et al. 2020

IJMS

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“…RT-QuIC Analysis. Tau RT-QuIC assays were conducted as previously described with minor modifications (Orru et al, 2017;Saijo et al, 2017;Kraus et al, 2019;Wang et al, 2019). In brief, each recombinant tau isoform was thawed at room temperature and filtered with a 100 kDa spin column filter (Millipore) to remove unwanted tau aggregates.…”

Section: Thioflavin-t Fluorescence Aggregationmentioning

confidence: 99%

“…Many protein misfolding diseases, such as AD and other tauopathies (Caughey & Lansbury, 2003), Parkinson's disease , type 2 diabetes , involve analogous pathological accumulation of disease-specific amyloidogenic protein in the form of self-seeding filaments or sub-filamentous deposits. Two methods to amplify misfolded proteins in vitro, the real-time quaking-induced conversion (RT-QuIC) assay and the protein misfolding cyclic amplification protocol (PMCA) are used for ultrasensitive detection in a number of neurodegenerative diseases, such as prion disease (Moda et al, 2014;Orru et al, 2017;Wang et al, 2019), Ab oligomers in AD (Salvadores et al, 2014), and a-synuclein in Parkinson's disease (Fairfoul et al, 2016;Shahnawaz et al, 2017;Groveman et al, 2018). Specifically for misfolded tau detection in AD and other tauopathies such as Pick's disease, detection of the prion-like tau seeding activities by RT-QuIC assays was successfully developed using engineered short fragments of tau or a mixture of tau fragments with mutations as a substrate (Saijo et al, 2017;Kraus et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Human Tau Isoform Aggregation and Selective Detection of Misfolded Tau from Post-Mortem Alzheimer’s Disease Brains

Wang

Lad

et al. 2020

Preprint

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Tau aggregates are present in a large number of neurodegenerative diseases known as "tauopathies", including Alzheimer's disease (AD). As there are six human tau isoforms in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions, we tested whether tau isoforms behave differently in aggregation. We discovered that all six tau isoforms are capable of forming PHF-tau like filaments and the 3R tau isoforms aggregate significantly faster than their 4R counterparts. We further mapped key segments of tau isoforms that contribute to their aggregation kinetics, where it was determined that microtubule binding domains R2 and R3 were the major contributors to tau aggregation. To evaluate the feasibility of using the six recombinant tau isoforms as substrates to amplify misfolded tau, we demonstrated that full-length human tau isoforms can seed and detect misfolded tau from the post-mortem AD brain tissues with high specificity by an ultrasensitive technology termed real-time quaking-induced conversion (RT-QuIC). Mass spectrometric analysis of PHF-tau samples extracted from AD brains identified peptides corresponding to all major forms of human brain tau isoforms along with a consensus hyperphosphorylated peptide near the C-terminus.Together, our findings not only reveal new aggregation kinetic properties of human tau isoforms, support the development of methods to quantitatively measure misfolded human tau isoforms in AD brains, but also uncover the capability of full-length human tau isoforms as substrates for "prion-like" tau seeding by RT-QuIC assays that may be used for new biomarker development for AD and other tauopathy diagnosis.

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“…Given the generalized spread of prions throughout the body for certain prion strains and their presence in highly innervated tissues [266], skeletal muscle, and skin have been also tested for presence of prions. In skin, it seems to be associated to peripheral nerves rather than keratinocytes and has been detected by immunoblotting in scrapie-infected sheep [322], in patients with vCJD [323] and in sCJD patients by bioassay and RT-QuIC [324], and also by RT-QuIC in animal models infected with sCJD, even at pre-clinical stages [325]. Therefore, skin biopsy-based diagnostic test could be feasible soon.…”

Section: Detection Of Prp Sc In Other Tissues and Body Fluidsmentioning

confidence: 99%

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

et al. 2020

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Transmissible spongiform encephalopathies or prion diseases are rapidly progressive neurodegenerative diseases, the clinical manifestation of which can resemble other promptly evolving neurological maladies. Therefore, the unequivocal ante-mortem diagnosis is highly challenging and was only possible by histopathological and immunohistochemical analysis of the brain at necropsy. Although surrogate biomarkers of neurological damage have become invaluable to complement clinical data and provide more accurate diagnostics at early stages, other neurodegenerative diseases show similar alterations hindering the differential diagnosis. To solve that, the detection of the pathognomonic biomarker of disease, PrP Sc , the aberrantly folded isoform of the prion protein, could be used. However, the amounts in easily accessible tissues or body fluids at pre-clinical or early clinical stages are extremely low for the standard detection methods. The solution comes from the recent development of in vitro prion propagation techniques, such as Protein Misfolding Cyclic Amplification (PMCA) and Real Time-Quaking Induced Conversion (RT-QuIC), which have been already applied to detect minute amounts of PrP Sc in different matrixes and make early diagnosis of prion diseases feasible in a near future. Herein, the most relevant tissues and body fluids in which PrP Sc has been detected in animals and humans are being reviewed, especially those in which cell-free prion propagation systems have been used with diagnostic purposes.

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Early preclinical detection of prions in the skin of prion-infected animals

Cited by 47 publications

References 42 publications

Neuroimmune Response in Natural Preclinical Scrapie after Dexamethasone Treatment

Neuroimmune Response in Natural Preclinical Scrapie after Dexamethasone Treatment

Human Tau Isoform Aggregation and Selective Detection of Misfolded Tau from Post-Mortem Alzheimer’s Disease Brains

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

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