Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death

Liu, Mengyu; Sui, Dexin; Dexheimer, Thomas S.; Hovde, Stacy; Deng, Xiexiong; Wang, Kuang Wei; Lin, Hsin Lian; Chien, Hsiao Tien; Kweon, Hye Kyong; Kuo, Nora Sheen; Ayoub, Christopher A.; Jiménez, Daniela Mora; Andrews, Philip C.; Kwok, Roland P.S.; Bochar, Daniel A.; Kuret, Jeff; Fortin, Jessica S.; Tsay, Yeou Guang; Kuo, Min Hao

doi:10.1007/s12035-020-02034-w

Cited by 33 publications

(70 citation statements)

References 93 publications

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“…1). As described in "Introduction" above, we have produced hyperphosphorylated 1N4R tau (p-tau) in E. coli that possessed AD pathology-associated phosphoepitopes, and formed cytotoxic aggregates without an inducer 60 . These characters were absent in unmodified tau, suggesting the possibility of identifying new categories of compounds for the control of hyperphosphorylation-driven behaviors of tau.…”

Section: Screen Of a 1280-compound Library Identified P-tau Aggregatimentioning

confidence: 99%

“…Of the 9 PTAIs, R-(−)apomorphine and raloxifene were selected for further studies for three reasons. Firstly, we took advantage of the cytotoxicity of p-tau 60 (detailed below) to evaluate whether these compounds modulated p-tau cytotoxicity without the use of the fibril dye, ThS, or any inducer. Three PTAIs [R-(−)apomorphine, idebenone and raloxifene] reduced p-tau cytotoxicity and both PTAEs showed enhancement (Table 1 and Supplemental Fig.…”

Section: Screen Of a 1280-compound Library Identified P-tau Aggregatimentioning

confidence: 99%

“…Many "hits" from prior tau-based HTS were non-selective redox modulators 49 , due most likely to the susceptibility of unmodified tau fibrils to the oxidation of two cysteine residues of tau, C291 and C322. Because p-tau aggregation was not affected by changing the two cysteine residues to alanine or serine 60 , we suspected that R-(−)-apomorphine and raloxifene would act independently of these two cysteine. Figure 3c and Supplemental Fig.…”

Section: Screen Of a 1280-compound Library Identified P-tau Aggregatimentioning

confidence: 99%

“…It was therefore concluded that R-(−)-apomorphine and raloxifene antagonized p-tau aggregation in a mechanism(s) not related to the two cysteine residues of p-tau. Another unique character of p-tau that is relevant to AD pathology is that p-tau causes cell death at submicromolar concentrations 60 (see below). If this cytotoxicity is part of the underlying reasons for neurodegeneration, PTAIs that quenched p-tau cytotoxicity would be better candidates to be funneled through further development.…”

Section: Screen Of a 1280-compound Library Identified P-tau Aggregatimentioning

confidence: 99%

“…The efficiency, yield, and the purity of the final phosphorylated tau protein were usually insufficient to support the throughput necessary for drug screen. We recently used the PIMAX approach (Protein Interaction Modules-Assisted function X) 59 for the synthesis of hyperphosphorylated tau (p-tau) in E. coli 60 . This 1N4R p-tau possessed multiple phosphorylation marks for the staging of AD brain samples.…”

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confidence: 99%

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Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions

Liu

Dexheimer

Sui

et al. 2020

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The neurodegenerative Alzheimer’s disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(−)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(−)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.

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Section: Screen Of a 1280-compound Library Identified P-tau Aggregatimentioning

confidence: 99%

Section: Screen Of a 1280-compound Library Identified P-tau Aggregatimentioning

confidence: 99%