Visualization of soluble tau oligomers in TauP301L-BiFC transgenic mice demonstrates the progression of tauopathy

Shin, Sera; Kim, Do-Hee; Song, Ji Yeon; Jeong, Hyeanjeong; Hyeon, Seung Jae; Kowall, Neil W.; Ryu, Hoon; Pae, Ae Nim; Lim, Sungsu; Kim, Yun Kyung

doi:10.1016/j.pneurobio.2020.101782

Cited by 29 publications

(34 citation statements)

References 65 publications

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“…Tau oligomers often are considered the most toxic form of the protein (60,61). Mouse studies have shown that memory loss and synapse loss correlated better with oligomer concentration levels than with the amount or spreading of NFTs (62,63). In view of these data, we tested whether CLR01 treatment affected tau-oligomer levels using dot-blots and native-PAGE/western-blot analyses in the soluble fraction of the brain extracts.…”

Section: Clr01 Reduces Tau Oligomers In the Hippocampus Dose-dependentlymentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

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Background: Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3×Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for one month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3×Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left the question whether CLR01 affected tau in vivo directly or indirectly open.Methods: To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3- or 1.0-mg/Kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.Results: CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.Conclusions: The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ) and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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Section: Clr01 Reduces Tau Oligomers In the Hippocampus Dose-dependentlymentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Tau oligomers often are considered the most toxic form of the protein [60,61]. Mouse studies have shown that memory loss and synapse loss correlated better with oligomer concentration levels than with the amount or spreading of NFTs [62,63]. In view of these data, we tested whether CLR01 treatment affected tau-oligomer levels using dot-blots and native-PAGE/western-blot analyses in the soluble fraction of the brain extracts.…”

Section: Clr01 Reduces Tau Oligomers In the Hippocampus Dosedependentlymentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2021

Alz Res Therapy

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Background Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly. Methods To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology. Results CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures. Conclusions The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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“…1 d). In contrast, in AD model mice overexpressing mutant tau, such as tau fused with bimolecular fluorescence complementation (tau-BiFC), and triple transgenic mice (APP, PS1, and tau-BiFC (3×TG)) [ 24 ], c-proteasome activity decreased compared to controls (Unpaired t -test, p = 0.040 and = 0.026, respectively; N = 9) ( Fig. 1 d).…”

Section: Resultsmentioning

confidence: 99%

“…Generation of APP/PS1 was as previously described [ 23 ]. To generate APP/PS1/Tau-BiFC transgenic mouse, hemizygous APP/PS1 mice harboring APPswe and PSEN1M146V, were crossed with hemizygous TauP301L-BiFC mice that express the human TauP301L-BiFC (TauP301L-VC155 and TauP301L-VN173) [ 24 ]. Littermates that were negative for the APPswe, PSEN1M146V, and TauP301L-BiFC were used for wild-type control.…”

Section: Methodsmentioning

confidence: 99%

Proteasome Activity in the Plasma as a Novel Biomarker in Mild Cognitive Impairment with Chronic Tinnitus

Yun

Lee

Choi

et al. 2020

JAD

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Background: Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown. Objective: Given that c-proteasome activity was significantly reduced in Alzheimer’s disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus. Methods: c-Proteasome activity in the plasma of tinnitus patients (N = 55) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ42, and Aβ40 were measured using ELISA, and their association with c-proteasome activity was evaluated. Results: The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus. Conclusion: Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis.

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Visualization of soluble tau oligomers in TauP301L-BiFC transgenic mice demonstrates the progression of tauopathy

Cited by 29 publications

References 65 publications

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Proteasome Activity in the Plasma as a Novel Biomarker in Mild Cognitive Impairment with Chronic Tinnitus

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