A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer’s Disease

Article type: Research Article

Authors: Akhter, Hasina^a | Huang, Wen-Tan^a | van Groen, Thomas^b | Kuo, Hui-Chien^c | Miyata, Toshio^d | Liu, Rui-Ming^{a; e; *}

Affiliations: [a] Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA | [b] Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA | [c] Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA | [d] United Centers for Advanced Research and Translational Medicine, Tohoku University, Tohoku, Japan | [e] Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: [*] Correspondence to: Rui-Ming Liu, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Tel.: +1 205 934 7028; Fax: +1 205 934 1721; E-mail: [email protected].

Abstract: Alzheimer’s disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

Keywords: Alzheimer’s disease, amyloid-β accumulation, memory, PAI-1 inhibitor

DOI: 10.3233/JAD-180241

Journal: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 447-457, 2018