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

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.

Key inflammatory pathway activations in the MCI stage of Alzheimer’s disease

“…The main consequences of the activation of this pathway are the opsonization of pathogens, the recruitment of inflammatory and immunocompetent cells, and the direct killing of pathogens . The association between levels of these analytes and A β burden has been noted in multiple previous studies . Among the other inflammatory analytes of significance in our results, the relationships between AD diagnosis and CCL2, MMP2, and VGEF have been previously reported, whereas VCAM1 has been reported in relation to both AD and vascular cognitive impairment …”

Identification of inflammatory and vascular markers associated with mild cognitive impairment

“…Metabolic and vascular mechanisms have been suggested to contribute to MCI and dementia, yet the previous studies displayed discrepant results [33,34]. We explored the potential role of aberrant metabolism and vascular function in MCI by measuring plasma levels of promising markers, including PAI-1, C-peptide and VEGF-A.…”

Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications

“…Interestingly, a recent study has shown that administration of a PAI‐1 inhibitor for a period of 6 weeks reduces Aβ load in the hippocampus and cortex and improve learning and memory function in an AD mouse model . Notably, these effects were associated with increased tPA and plasmin activities.…”