Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease

Theendakara, Veena; Bredesen, Dale E.; Rao, Rammohan V.

doi:10.1016/j.mcn.2017.07.002

Cited by 36 publications

(22 citation statements)

References 47 publications

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“…Speci cally in the high aluminum AD model, the activity of PP2A decreased by 59% (65). Further studies showed that the accumulation of zinc ions and the expression of APOE were the pathological factors for decreasing the activity of PP2A (66,67). Due to the decrease of PP2A, the phosphorylation of tau is increased by activating GSK3β (68).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

Guan

Wang

2020

Preprint

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Background: Prostaglandin (PG) A1 is a metabolic product of cyclooxygenase 2 (COX-2), which potentially involved in regulating the development and progression of Alzheimer’s disease (AD). As a cyclopentenone (cy) PG, PGA1 is characterized by the presence of a chemically reactive α, β-unsaturated carbonyl. Although PGA1 is potentially involved in regulating multiple biological processes via michael addition, its specific roles in AD remained unclear.Methods: The tauP301S transgenic (Tg) mice were employed as in vivo AD models and neuroblastoma (N) 2a cells as in vitro neuronal models. By intracerebroventricular injected (i.c.v) with PGA1, the binding proteins to PGA1 are analyzed by HPLC-MS-MS. In addition, western blots are used to determine the phosphorylation of tau in PGA1 treated Tg mice in the absence or presence of okadaic acid (OA), an inhibitor of protein phosphotase (PP) 2A. Combining a synthesis of pull down assay, immunoprecipitation, western blots and HPLC-MS-MS, PP2A scaffold subunit A alpha (PPP2R1A) was identified to be activated by directly binding on PGA1 in cysteine 377-dependent manner. Via inhibiting the hyperphosphorylation of tau, morris maze test was employed to determine the inhibitory effects of PGA1 on cognitive decline of tauP301S Tg mice.Results: By incubation with neuroblastoma (n)2a cells and pull down assay, mass spectra (MS) analysis revealed that PGA1 binds with more than 1000 proteins, among which contains the proteins of AD, especially tau protein. Moreover, short-term administration of PGA1 to tauP301S Tg mice significantly decreased the phosphorylation of tau at the sites of Thr181, Ser202 and Ser404 in a dose-dependent manner. To the reason, it’s caused by activating PPP2R1A in tauP301S Tg mice. More importantly, PGA1 has the ability to form michael adduct with PPP2R1A via its cysteine 377 motif, which is critical for the enzymatic activity of PP2A. By activating PP2A, long-term application of PGA1 to tauP301S Tg mice significantly reduced the phosphorylation of tau, which results in improving the cognitive decline of tauP301S Tg mice.Conclusion: Our data provided the first insights needed to decipher the mechanisms underlying the ameliorating effects of PGA1 on cognitive decline of tauP301S Tg mice via activating PP2A in a PPP2R1AC377-dependent Michael adducting mechanisms.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

Guan

Wang

2020

Preprint

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“…It is widely established that PP2A is the primary enzyme responsible for dephosphorylation of tau protein throughout the brain, controlling all tau phosphorylation sites. PP2A activity is decreased in AD and TBI brains (12, 82). Therefore, the OA-induced inhibition of PP2A is a highly relevant model to study various tau protein kinase inhibitors as modulators of tau hyperphosphorylation and oligomerization targeting tau pathology (Figure 6, Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…At least thirty tau phosphorylation sites have been reported in healthy conditions. Tau’s phosphorylation state and its ability to interact with microtubule proteins are regulated by various protein kinases and phosphatases (12, 13). Imbalances in the activities of tau kinases and phosphatases can cause tau to become hyperphosphorylated at specific residues leading to a higher tendency to dissociate from microtubules.…”

Section: Introductionmentioning

confidence: 99%

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

Yadikar

Torres

Aiello

et al. 2019

Preprint

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26Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of 27 post-translationally modified tau protein in the human brain. Tauopathies are associated with 28 Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. 29Hyperphosphorylation increases tau tendency to aggregate and forms neurofibrillary tangles 30 (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein 31 phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated 32 rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and 33 oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of 34 different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-35 immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), 36 pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation 37 and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric 38 bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl 39 (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) 40 caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX 41 culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator 42 (EGTA) showed conflicting results between the two neuronal cultures.This study provides a 43 comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their 44 efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant 45 further experimentation, possibly including animal models of tauopathies, which may provide a 46 putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative 47 diseases.48

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“…ApoE protein downregulates the level of PP2A in AD by transcriptional repression and reduces its activity by disrupting the PPP2R5E–PP2AC complex through demethylation of the catalytic subunit of PP2A. The low‐level PP2A activity results in accumulation of phosphorylated tau . Treatment of Tg mice with a small‐molecule kinase inhibitor, K252a (a staurosporine analogue), prevents tau hyperphosphorylation and motor defects (Figure E).…”

Section: Phosphorylationmentioning

confidence: 99%

Role of Post‐translational Modifications in Alzheimer's Disease

2020

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The global burden of Alzheimer's disease (AD) is growing. Valiant efforts to develop clinical candidates for treatment have continuously met with failure. Currently available palliative treatments are temporary and there is a constant need to search for reliable disease pathways, biomarkers and drug targets for developing diagnostic and therapeutic tools to address the unmet medical needs of AD. Challenges in drug‐discovery efforts raise further questions about the strategies of current conventional diagnosis; drug design; and understanding of disease pathways, biomarkers and targets. In this context, post‐translational modifications (PTMs) regulate protein trafficking, function and degradation, and their in‐depth study plays a significant role in the identification of novel biomarkers and drug targets. Aberrant PTMs of disease‐relevant proteins could trigger pathological pathways, leading to disease progression. Advancements in proteomics enable the generation of patterns or signatures of such modifications, and thus, provide a versatile platform to develop biomarkers based on PTMs. In addition, understanding and targeting the aberrant PTMs of various proteins provide viable avenues for addressing AD drug‐discovery challenges. This review highlights numerous PTMs of proteins relevant to AD and provides an overview of their adverse effects on the protein structure, function and aggregation propensity that contribute to the disease pathology. A critical discussion offers suggestions of methods to develop PTM signatures and interfere with aberrant PTMs to develop viable diagnostic and therapeutic interventions in AD.

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Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease

Cited by 36 publications

References 47 publications

Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

Role of Post‐translational Modifications in Alzheimer's Disease

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