Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

Zhou, Qiuzhi; Li, Shihong; Li, Mengzhu; Ke, Dan; Wang, Qun; Yang, Ying; Liu, Gongping; Wang, Xiaochuan; Liu, Enjie; Wang, Jian‐Zhi

doi:10.1016/j.ebiom.2022.103970

Cited by 32 publications

(24 citation statements)

References 57 publications

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“…We quantified phosphorylation levels of GSK3β and p38-MAPK, two important kinases phosphorylating tau proteins in neurons. 26,35 As shown in Figure 7A-D, neuronal IKKβ-deficient and wild-type 9-month-old tau-transgenic mice did not differ in phosphorylation of any of the enzymes (t test, p > .05), suggesting that the decrease in p-tau in IKKβ-deficient tau mice was probably not due to the reduction in p-tau generation. Interestingly, we observed that IKKβ deficiency significantly up-regulated the transcription of Ppp2ca, but not Ppp2cb, Ppp3ca, and Ppp3cb in the brain of tau-transgenic mice (Figure 7E-H; t test, p < .05), which was in line with a previous observation that NF-κB activation inhibits expression of catalytic subunit of PP2A (PP2Ac).…”

Section: Neuronal Deficiency Of Potentially Increases the Dephosphory...mentioning

confidence: 84%

“…Because the total amount of tau protein in the brain is not affected by neuronal IKKβ de ciency, the decrease in cerebral p-tau is more likely due to the reduced phosphorylation of tau. However, neuronal de ciency of IKKβ in our tau-transgenic mice affects the activation of neither p38α-MAPK nor GSK3β, two key kinases phosphorylating tau in AD [31,39]. We turned to consider the role of PP2A and -2B, as they dephosphorylate p-tau thereby regulating the cerebral p-tau level [53].…”

Section: Discussionmentioning

confidence: 99%

“…46 Our experiments showed that deletion of IKKβ in neurons attenuates both phosphorylated and total tau in brains of tau-transgenic mice. Because neuronal deficiency of IKKβ did not alter transcription of TAU gene, or activation of p38α-MAPK and GSK3β, two key kinases that phosphorylate tau in AD brain, 26,35 we hypothesized that the reduction in tau proteins might be due to increased dephosphorylation of tau and/or degradation of tau. PP2A and -2B are the enzymes dephosphorylating p-tau.…”

Section: Discussionmentioning

confidence: 99%

“…As IKKβ de ciency in neurons attenuated p-tau, but not t-tau in the brain of tau-transgenic mice, we hypothesized that IKKβ regulated the phosphorylation level of tau protein in AD mice. We quanti ed phosphorylation levels of GSK3β and p38-MAPK, two important kinases phosphorylating tau proteins in neurons [31,39]. As shown in Fig.…”

Section: Neuronal De Ciency Of Ikkβ Potentially Increases the Dephosp...mentioning

confidence: 99%

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Deficiency of IKKβ in neurons ameliorates Alzheimer's disease pathology in APP‐ and tau‐transgenic mice

Schnöder

Quan

et al. 2023

The FASEB Journal

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In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid‐β‐peptide (Aβ) and phosphorylated tau (p‐tau), as well as neurodegeneration; however, the regulatory mechanisms remain unclear. We constructed APP‐ and tau‐transgenic AD mice with deletion of IKKβ specifically in neurons, and observed that IKKβ deficiency reduced cerebral Aβ and p‐tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKβ decreased apoptosis and maintained synaptic proteins (e.g., PSD‐95 and Munc18‐1) in the brain and improved cognitive function only in APP‐transgenic mice, but not in tau‐transgenic mice. Additionally, IKKβ deficiency decreased BACE1 protein and activity in APP‐transgenic mouse brain and cultured SH‐SY5Y cells. IKKβ deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p‐tau, in the brain of tau‐transgenic mice. Interestingly, deficiency of IKKβ in neurons enhanced autophagy as indicated by the increased ratio of LC3B‐II/I in brains of both APP‐ and tau‐transgenic mice. Thus, IKKβ deficiency in neurons ameliorates AD‐associated pathology in APP‐ and tau‐transgenic mice, perhaps by decreasing Aβ production, increasing p‐tau dephosphorylation, and promoting autophagy‐mediated degradation of BACE1 and p‐tau aggregates in the brain. However, IKKβ deficiency differently protects neurons in APP‐ and tau‐transgenic mice. Further studies are needed, particularly in the context of interaction between Aβ and p‐tau, before IKKβ/NF‐κB can be targeted for AD therapies.

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Section: Neuronal Deficiency Of Potentially Increases the Dephosphory...mentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Neuronal De Ciency Of Ikkβ Potentially Increases the Dephosp...mentioning

confidence: 99%

See 2 more Smart Citations

Deficiency of IKKβ in neurons ameliorates Alzheimer's disease pathology in APP‐ and tau‐transgenic mice

Schnöder

Quan

et al. 2023

The FASEB Journal

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“…After 36-48 h, when plasmid expression reached its peak, HEK293-hTau cells were treated with 2JY-OBZ4 or Hup-A or DMSO. The plasmid pCDNA3.0-GSK-3β WT was a generous gift from Dr. Zhou Qiuzhi (Hubei Key Laboratory of Education Ministry of China, Wuhan, China) [ 66 ].…”

Section: Methodsmentioning

confidence: 99%

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

Guo

Huang

et al. 2022

Aging

Self Cite

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Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Aβ production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3β, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Aβ production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Aβ42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 μg/ml in vitro, which is more than two times higher than Hup-A. Together, 2JY-OBZ4 showed promising therapeutic effects in AD cell models through regulating multiple targets. The research provides a new candidate for the therapeutic development of AD.

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The emerging nontraditional roles for tau in the brain

Tseng,

Cohen

2023

Cytoskeleton

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Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

Cited by 32 publications

References 57 publications

Deficiency of IKKβ in neurons ameliorates Alzheimer's disease pathology in APP‐ and tau‐transgenic mice

Deficiency of IKKβ in neurons ameliorates Alzheimer's disease pathology in APP‐ and tau‐transgenic mice

Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets

The emerging nontraditional roles for tau in the brain

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