Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease

Protein phosphatase 2A(PP2A)is a major serine/threonine phosphatase which participates in the regulation of multiple cellular processes.As a confirmed tumor suppressor,PP2A activity is downregulated in tumors and its re-activation can induce apoptosis of cancer cells.In the brains of Alzheimer's disease(AD)patients,decreased PP2A activity also plays a key role in promoting tau hyperphosphorylation and A0 generation.In this review,we discussed compounds aiming at modulating PP2A activity in the treatment of cancer or AD.The upstream factors that inactivate PP2A in diseases have not been fully elucidated and further studies are needed.It will help for the refinement and development of novel and clinically tractable PP2A-targeted compounds or therapies for the treatment of tumor and AD.

Erratum to: Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and A zheimer's Disease

The article“Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease”,written by Hui WEI,Hui-liang ZHANG,Jia-zhao XIE,Dong-li MENG,Xiao-chuan WANG,Dan KE,Ji ZENG,Rong LIU,was originally published electronically on the publisher's internet portal on 13 March 2020 without open access.With the author(s)'decision to opt for Open Choice the copyright of the article changed to O The Author(s)2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License(https://creativecommons.org/licenses/by/4.0/),which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons license,and indicate if changes were made.

Correction:A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimerlike pathology

After online publication of the article',the authors noticed that,owing to authors'oversight in layer placement within the illustration,Golgi staining images representing both the 5xFAD group and,the 5xFAD+IDH3β_group were unintentionally duplicated in Fig.7e;In Fig.8b,11-month-old mice were incorrectly written as 12-month-old.

A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

Impaired brain glucose metabolism is an early indicator of Alzheimer’s disease(AD);however,the fundamental mechanism is unknown.In this study,we found a substantial decline in isocitrate dehydrogenase 3β(IDH3β)levels,a critical tricarboxylic acid cycle enzyme,in AD patients and AD-transgenic mice’s brains.Further investigations demonstrated that the knockdown of IDH3βinduced oxidation-phosphorylation uncoupling,leading to reduced energy metabolism and lactate accumulation.The resulting increased lactate,a source of lactyl,was found to promote histone lactylation,thereby enhancing the expression of paired-box gene 6(PAX6).As an inhibitory transcription factor of IDH3β,the elevated PAX6 in turn inhibited the expression of IDH3β,leading to tau hyperphosphorylation,synapse impairment,and learning and memory deficits resembling those seen in AD.In AD-transgenic mice,upregulating IDH3βand downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies.Collectively,our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β.Breaking this loop by upregulating IDH3βor downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.

Liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting

Hyperhomocysteinemia(Hhcy)is an independent risk factor for Alzheimer's disease(AD),and insulinresistance is commonly seen in patients with Hhcy.Liraglutide(Lir),a glucagon-like peptide that increases the secretion and sensitivity of insulin,has a neurotrophic or neuroprotective effect.However,it is not known whether Lir ameliorates the AD-like pathology and memory deficit induced by Hhcy.By vena caudalis injection of homocysteine to produce the Hhcy model in rats,we found here that simultaneous administration of Lir for 2 weeks ameliorated the Hhcy-induced memory deficit,along with increased density of dendritic spines and up-regulation of synaptic proteins.Lir also attenuated the Hhcy-induced tau hyperphosphorylation and Aβ overproduction,and the molecular mechanisms involved the restoration of protein phosphatase-2 A activity and inhibition of β-and γ-secretases.Phosphorylated insulin receptor substrate-1 also decreased after treatment with Lir.Our data reveal that Lir improves the Hhcy-induced AD-like spatial memory deficit and the mechanisms involve the modulation of insulinresistance and the pathways generating abnormal tau and Aβ.