TGF-β1 Restores Hippocampal Synaptic Plasticity and Memory in Alzheimer Model via the PI3K/Akt/Wnt/β-Catenin Signaling Pathway
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Alzheimer’s disease (AD) is the most common neurodegenerative disturbances. Dysfunction of synaptic plasticity and decline in cognitive functions are the most prominent features of AD, but the mechanisms of pathogenesis have not been well elucidated. In this paper, transforming growth factor-β1 (TGF-β1) was found to be reduced in the hippocampus of AD mouse which was accompanied by impaired pine density, synaptic plasticity, and memory function. Hippocampal injection of TGF-β1 rescued the AD-induced memory function impairment. In addition, TGF-β1 ameliorated synaptic plasticity and increased synaptic plasticity-associated protein expression including Arc, NR2B, and PSD-95 in mouse model of AD. Furthermore, we demonstrated that Akt/Wnt/β-catenin pathway protein expression in the hippocampus was suppressed in a mouse model of AD and TGF-β1 significantly enhanced the phosphorylation Akt, GSK3β, and increased the nuclear β-catenin. These results indicate that TGF-β1activates PI3K/Akt/Wnt/β-catenin signaling in mouse model of AD, which is important for promoting synaptic plasticity related to memory function. More importantly, suppression of PI3K/Akt/Wnt/β-catenin pathway compromised the beneficial effects of TGFβ1 in Alzheimer’s model. Hence, TGF-β1 shows protective effect on neurons, which might be through the PI3K/Akt/Wnt/β-catenin signaling pathway, serving as a potential target in AD pathology.
KeywordsTGF-β1 Alzheimer’s disease PI3K/Akt/Wnt/β-catenin Cognitive functions
This work was supported by Key R & D plan of Guangxi Science and Technology Plan (No. AB16380324-02); Systematic Subject of Guangxi Key Laboratory of Basic Research of Chinese Medicine (No. 16-380-58-04); Youth Innovation Research Team of Guangxi University of Traditional Chinese Medicine (No. 2016QT004); Project Support for High Level Talent Team Development in Qi Huang Engineering of Guangxi University of Traditional Chinese Medicine (No. 2018003).
Compliance with Ethical Standards
The study protocols were approved by the relevant ethics committee of The First Affiliated Hospital of Guangxi University of Chinese Medicine, and all study procedures were performed in accordance with corresponding regulations regarding the Use of Laboratory Animals.
Conflict of Interest
The authors declare that they have no conflict of interests.
- Caraci F, Bosco P, Signorelli M, Spada RS, Cosentino FI, Toscano G, Bonforte C, Muratore S, Prestianni G, Panerai S, Giambirtone MC, Gulotta E, Romano C, Salluzzo MG, Nicoletti F, Copani A, Drago F, Aguglia E, Ferri R (2012) The CC genotype of transforming growth factor-beta1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression. Eur Neuropsychopharmacol 22:281–289CrossRefGoogle Scholar
- Caraci F, Tascedda F, Merlo S, Benatti C, Spampinato SF, Munafò A, Leggio GM, Nicoletti F, Brunello N, Drago F, Sortino MA, Copani A (2016) Fluoxetine Prevents Abeta1–42-Induced Toxicity via a Paracrine Signaling Mediated by Transforming-Growth-Factor-beta1. Front Pharmacol 7:389CrossRefGoogle Scholar
- Chen JH, Ke KF, Lu JH, Qiu YH, Peng YP (2015) Protection of TGF-beta1 against neuroinflammation and neurodegeneration in Abeta1-42-induced Alzheimer's disease model rats. PLoS One 10:e116549Google Scholar
- Knopman DS, Haeberlein SB, Carrillo MC, Hendrix JA, Kerchner G, Margolin R, Maruff P, Miller DS, Tong G, Tome MB, Murray ME, Nelson PT, Sano M, Mattsson N, Sultzer DL, Montine TJ, Jack CR Jr, Kolb H, Petersen RC, Vemuri P, Canniere MZ, Schneider JA, Resnick SM, Romano G, van Harten AC, Wolk DA, Bain LJ, Siemers E (2018) The National Institute on Aging and the Alzheimer's Association research framework for Alzheimer's disease: perspectives from the research roundtable. Alzheimers Dement 14:563–575CrossRefGoogle Scholar
- Ongali B, Nicolakakis N, Tong XK, Lecrux C, Imboden H, Hamel E (2018) Transforming growth factor-beta1 (TGF-beta1) induces cerebrovascular dysfunctionand astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways. Can J Physiol Pharmacol 96:527–534Google Scholar
- Pan Y, Nicolazzo JA (2018) Impact of aging, Alzheimer’s disease and Parkinson’s disease on the blood-brain barrier transport of therapeutics. Adv Drug Deliv Rev 135:62–74Google Scholar