1. Pharmacological inhibition of plasminogen activator inhibitor-1 prevents memory deficits and reduces neuropathology in APP/PS1 mice.
- Author
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Rodriguez G, Eren M, Haupfear I, Viola KL, Cline EN, Miyata T, Klein WL, Vaughan DE, and Dong H
- Subjects
- Mice, Humans, Animals, Infant, Mice, Transgenic, Plaque, Amyloid metabolism, Plasminogen Activator Inhibitor 1 metabolism, Plasminogen Activator Inhibitor 1 therapeutic use, Memory Disorders drug therapy, Memory Disorders prevention & control, Memory Disorders complications, Disease Models, Animal, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Presenilin-1 genetics, Amyloid beta-Peptides metabolism, Alzheimer Disease metabolism
- Abstract
Rationale: Extracellular proteolytic activity plays an important role in memory formation and the preservation of cognitive function. Previous studies have shown increased levels of plasminogen activator inhibitor-1 (PAI-1) in the brain of mouse models of Alzheimer's disease (AD) and plasma of AD patients, associated with memory and cognitive decline; however, the exact function of PAI-1 in AD onset and progression is largely unclear., Objective: In this study, we evaluated a novel PAI-1 inhibitor, TM5A15, on its ability to prevent or reverse memory deficits and decrease Aβ levels and plaque deposition in APP/PS1 mice., Methods: We administered TM5A15 mixed in a chow diet to 3-month and 9-month-old APP/PS1 mice before and after neuropathological changes were distinguishable. We then evaluated the effects of TM5A15 on memory function and neuropathology at 9 months and 18 months of age., Results: In the younger mice, 6 months of TM5A15 treatment protected against recognition and short-term working memory impairment. TM5A15 also decreased oligomer levels and amyloid plaques, and increased mBDNF expression in APP/PS1 mice at 9 months of age. In aged mice, 9 months of TM5A15 treatment did not significantly improve memory function nor decrease amyloid plaques. However, TM5A15 treatment showed a trend in decreasing oligomer levels in APP/PS1 mice at 18 months of age., Conclusion: Our results suggest that PAI-1 inhibition could improve memory function and reduce the accumulation of amyloid levels in APP/PS1 mice. Such effects are more prominent when TM5A15 is administered before advanced AD pathology and memory deficits occur., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
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