Time- and dose-dependent seeding tendency of exogenous tau R2 and R3 aggregates in cells

Annadurai, Narendran; Hrubý, Jiří; Kubíčková, Agáta; Malina, Lukáš; Hajdúch, Marián; Das, Viswanath

doi:10.1016/j.bbrc.2023.02.057

Cited by 3 publications

(10 citation statements)

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“…1A, B). This failure in autophagy in response to the aggregate-induced proteotoxic stress possibly causes the buildup of intracellular aggregates, as observed in our previous study [27,28].…”

Section: Exogenous R2 and R3 Fibrils Affect Autophagy And The Growth ...supporting

confidence: 69%

“…When exposed to fibrils, cells become vulnerable to an increased burden of seeding, resulting in autophagy failure to remove the intracellular aggregates. The difference in autophagy timeline between R2 and R3-induced cells might result from the burden of aggregate load, as we have reported that R2 fibrils have a more significant seeding potency than R3 fibrils [28]. The defects in LC3-I/II conversion were also accompanied by increased p62 levels, which showed a trend of time-dependent increase, particularly in R3-induced cells (Fig.…”

Section: Resultsmentioning

confidence: 81%

“…We have recently shown that R2 and R3 cause a time- and dose-dependent increase in total- and pSer262- tau levels in triton-insoluble fractions of induced cells [28]. In addition, we have also shown that the presence of P301S mutation in biosensor cells enhanced pSer262 tau even in triton-soluble fractions, and P301S Tau is prone to aggregate into insoluble fractions upon exposure to exogenous R2 and R3 fibrils [27,28]. The pSer262-containing intracellular aggregates in R2 and R3-induced cells were also seed-competent [27].…”

Section: Resultsmentioning

confidence: 99%

“…Cells expressing P301L-tau have been shown to escape all three types of autophagy, such as macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy-mediated degradation [18]. In addition, we have recently shown the enhanced conversion of soluble phosphorylated Ser262 tau into insoluble inclusions in R2 and R3-induced P301S-tau expressing cells [27,28]. In this study, we show that intracellular phosphorylated tau inclusions in R2- and R3-induced cells resist the aggregate-clearing mechanism and that failed autophagy is one of the mechanisms responsible for intracellular accumulation of aggregates.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in 4R tauopathies that result in conformational changes exposing the Repeat 2 (R2) domain, which harbours the VQIINK motif, may contribute to the pronounced pathology associated with 4R tauopathies compared to 3R tauopathies lacking the R2 domain [19,[24][25][26]. We have recently shown that the R2 fibrillizes faster than the Repeat 3 (R3) domain, and R2 aggregates have a greater propensity to seed native tau aggregation in cells than R3 aggregates [27,28]. This increased propensity is unsurprising, as the VQIINK motif in R2 is a more potent driver of tau aggregation than the VQIVYK motif in R3 [24].…”

Section: Introductionmentioning

confidence: 99%

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Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells

Annadurai,

Kubíčková,

Frydrych

et al. 2023

Preprint

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Aggregation of misfolded tau protein is a common feature of tauopathies. Cells employ diverse mechanisms to eliminate misfolded tau with different conformations, contributing to the varied clinical and pathological manifestations of tauopathies. This study focuses on the clearance of seeded tau aggregates following the induction of biosensor cells with R2 and R3 fibrils that exhibit distinct aggregation kinetics and seeding potencies. Our hypothesis is that the dissimilarity in time-dependent intracellular seeding induced by R2 and R3 fibrils underlies the variation in autophagy failure. These discrepancies may account for the heterogeneity of pathology and disease progression between 3R and 4R tauopathies, given the absence of R2 in 3R tau isoforms. In R2-induced cells, alterations in p62 and LC3II/I levels, indicative of proteotoxic stress and autophagy failure, occur sooner than in R3-induced cells. Conversely, LAMP1 levels remained unaffected, suggesting a failure in the fusion of aggregate-containing autophagosomes with lysosomes. This autophagic failure may increase seed-dependent intracellular aggregation in induced cells. Consequently, we assessed the impact of autophagy inducers on the clearance of intracellular tau aggregates in induced cells. Epigallocatechin gallate (EGCG) demonstrated the highest efficacy in inducing autophagy and reducing p62 levels, decreasing seeding and clearing aggregates. Overall, this study elucidates the differential effects of prion-like R2 and R3 strains on autophagy and highlights how compounds like EGCG can selectively reduce tau aggregation to treat specific tauopathies. We provide insights into the distinct mechanisms of autophagy failure and autophagy clearance of intracellular aggregates in cells induced with R2 and R3 fibrils.

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Section: Exogenous R2 and R3 Fibrils Affect Autophagy And The Growth ...supporting

confidence: 69%

Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells

Annadurai,

Kubíčková,

Frydrych

et al. 2023

Preprint

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Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer’s disease inPrnpmutant mice and in the P301S transgenic tauopathy mice model

Sala-Jarque,

Gil,

Andrés-Benito

et al. 2024

Preprint

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The natural cellular prion protein is known to play several roles during development and adult brain. Far from its pathological roles in prionopathies, the non-pathogenic cellular prion protein has been described as a receptor for several amyloid in oligomeric and prefibrillar forms. For some amyloids, specific domains of the protein play a crucial role in modulating amyloid's cellular uptake and seeding properties. In most studies, the functions and the role of putative amyloid receptors have been analyzed by using brain extracts derived from human neurodegenerative patients. Another strategy has been to modify the genetic dosage of the natural prion protein in genetic models of different diseases. In this study, we take advantage of both approaches to examine whether this protein plays a role in the seeding and spreading of pathogenic tau. Our results point to a role of the natural prion protein in the emergence of pathogenic tau in a mouse model overexpressing the mutation P301S of the human tau gene. In contrast, its role is minor when sarkosyl-derived brain samples of Alzheimer's disease are used. In fact, our results indicate that the use of this type of sample is not adequate to determine the role of a putative receptor in tau seeding and spreading.

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Inflammation, Autoimmunity and Neurodegenerative Diseases, Therapeutics and Beyond

Garmendia,

De Sanctis,

Das

et al. 2024

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Neurodegenerative disease (ND) incidence has recently increased due to improved life expectancy. Alzheimer's (AD) or Parkinson's disease (PD) are the most prevalent NDs. Both diseases are poly genetic, multifactorial and heterogenous. Preventive medicine, a healthy diet, exercise, and controlling comorbidities may delay the onset. After the diseases are diagnosed, therapy is needed to slow progression. Recent studies show that local, peripheral and age-related inflammation accelerates NDs' onset and progression. Patients with autoimmune disorders like inflammatory bowel disease (IBD) could be at higher risk of developing AD or PD. However, no increase in ND incidence has been reported if the patients are adequately diagnosed and treated. Autoantibodies against abnormal tau, β amyloid and α- synuclein have been encountered in AD and PD and may be protective. This discovery led to the proposal of immune-based therapies for AD and PD involving monoclonal antibodies, immunization/vaccines, pro-inflammatory cytokine inhibition and anti-inflammatory cytokine addition. All the different approaches have been analysed here. Future perspectives on new therapeutic strategies for both disorders are concisely examined.

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Time- and dose-dependent seeding tendency of exogenous tau R2 and R3 aggregates in cells

Cited by 3 publications

References 4 publications

Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells

Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer’s disease inPrnpmutant mice and in the P301S transgenic tauopathy mice model

Inflammation, Autoimmunity and Neurodegenerative Diseases, Therapeutics and Beyond

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