PMID- 32096091 OWN - NLM STAT- MEDLINE DCOM- 20210901 LR - 20240204 IS - 1878-7479 (Electronic) IS - 1933-7213 (Print) IS - 1878-7479 (Linking) VI - 17 IP - 3 DP - 2020 Jul TI - Direct Activation of Protein Phosphatase 2A (PP2A) by Tricyclic Sulfonamides Ameliorates Alzheimer's Disease Pathogenesis in Cell and Animal Models. PG - 1087-1103 LID - 10.1007/s13311-020-00841-6 [doi] AB - Alzheimer's disease (AD) is a multifactorial neurodegenerative disease for which there are limited therapeutic strategies. Protein phosphatase 2A (PP2A) activity is decreased in AD brains, which promotes the hyperphosphorylation of Tau and APP, thus participate in the formation of neurofibrillary tangles (NFTs) and beta-amyloid (Abeta) overproduction. In this study, the effect of synthetic tricyclic sulfonamide PP2A activators (aka SMAPs) on reducing AD-like pathogenesis was evaluated in AD cell models and AD-like hyperhomocysteinemia (HHcy) rat models. SMAPs effectively increased PP2A activity, and decreased tau phosphorylation and Abeta(40/42) levels in AD cell models. In HHcy-AD rat models, cognitive impairments induced by HHcy were rescued by SMAP administration. HHcy-induced tau hyperphosphorylation and Abeta overproduction were ameliorated through increasing PP2A activity on compound treatment. Importantly, SMAP therapy also prevented neuronal cell spine loss and neuronal synapse impairment in the hippocampus of HHcy-AD rats. In summary, our data reveal that pharmacological PP2A reactivation may be a novel therapeutic strategy for AD treatment, and that the tricyclic sulfonamides constitute a novel candidate class of AD therapeutic. FAU - Wei, Hui AU - Wei H AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Zhang, Hui-Liang AU - Zhang HL AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Wang, Xiao-Chuan AU - Wang XC AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Xie, Jia-Zhao AU - Xie JZ AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - An, Dan-Dan AU - An DD AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Wan, Lu AU - Wan L AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Wang, Jian-Zhi AU - Wang JZ AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Zeng, Yi AU - Zeng Y AD - Clinical Laboratory, The Central Hospital of Wuhan, Wuhan, China. FAU - Shu, Xi-Ji AU - Shu XJ AD - Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China. FAU - Westermarck, Jukka AU - Westermarck J AD - Turku Bioscience Centre, University of Turku and Abo Akademi University, Turku, Finland. AD - Institute of Biomedicine, University of Turku, Turku, Finland. FAU - Lu, You-Ming AU - Lu YM AD - The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China. FAU - Ohlmeyer, Michael AU - Ohlmeyer M AD - Icahn School of Medicine at Mount Sinai, New York, NY, USA. michael.ohlmeyer@gmail.com. AD - Atux Iskay LLC, Plainsboro, NJ, USA. michael.ohlmeyer@gmail.com. FAU - Liu, Rong AU - Liu R AUID- ORCID: 0000-0001-7477-6520 AD - Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. rong.liu@hust.edu.cn. AD - The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China. rong.liu@hust.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Neurotherapeutics JT - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics JID - 101290381 RN - 0 (Sulfonamides) RN - 0LVT1QZ0BA (Homocysteine) RN - EC 3.1.3.16 (Protein Phosphatase 2) SB - IM MH - Alzheimer Disease/chemically induced/*drug therapy/*metabolism MH - Animals MH - *Disease Models, Animal MH - HEK293 Cells MH - Homocysteine/toxicity MH - Humans MH - Male MH - Protein Phosphatase 2/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Sulfonamides/chemistry/pharmacology/*therapeutic use PMC - PMC7609734 OTO - NOTNLM OT - Alzheimer's disease OT - PP2A OT - PP2A activator OT - SMAP OT - tau OT - beta-Amyloid COIS- Mount Sinai School of Medicine has filed patents on DBK-1154, DBK-1160 and related PP2A activating compounds. Other authors declare that they have no conflict of interest. EDAT- 2020/02/26 06:00 MHDA- 2021/09/02 06:00 PMCR- 2021/07/01 CRDT- 2020/02/26 06:00 PHST- 2020/02/26 06:00 [pubmed] PHST- 2021/09/02 06:00 [medline] PHST- 2020/02/26 06:00 [entrez] PHST- 2021/07/01 00:00 [pmc-release] AID - S1878-7479(23)01326-0 [pii] AID - 841 [pii] AID - 10.1007/s13311-020-00841-6 [doi] PST - ppublish SO - Neurotherapeutics. 2020 Jul;17(3):1087-1103. doi: 10.1007/s13311-020-00841-6.