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Pharmacological inhibition of plasminogen activator inhibitor-1 prevents memory deficits and reduces neuropathology in APP/PS1 mice

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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.

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Acknowledgements

This study was supported by the National Institution of Aging (1R01AG062249, Dong) and the National Heart, Lung, and Blood Institute (R01HL051387, Vaughan).

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 7-103, Chicago, IL, 60611, USA

    Guadalupe Rodriguez, Isabel Haupfear & Hongxin Dong

  2. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Mesut Eren & Douglas E. Vaughan

  3. Department of Neurobiology, Northwestern University, 2205 Tech Drive, Hogan 4-160, Evanston, IL, 60208, USA

    Kirsten L. Viola, Erika N. Cline & William L. Klein

  4. Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Toshio Miyata

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  1. Guadalupe Rodriguez
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ESM 1

S. Figure 1. TM5A15 intake and body weight in wild-type and APP/PS1 mice. A. The body weight of mice measured before and after 6 months of the vehicle or TM5A15 treatment. Mice showed no significant change in body weight between groups. B. Food intake of vehicle and TM5A15 was measured weekly. Weekly measurements showed no difference in food intake between groups that were treated for 6 months. C. The body weight of mice was measured before and after 9 months of the vehicle or TM5A15 treatment. Mice showed no significant change in body weight between groups. D. Food intake of the vehicle and TM5A15 was measured weekly. Weekly measurements showed no difference in food intake between groups that were treated for 9 months. (PDF 106 kb)

ESM 2

S. Figure 2. PAI-1 activity levels on WT and APP/PS1 after completion of the vehicle and TM5A15 treatment. Data are presented as Mean±SEM, n=14, * p= 0.0361. (PDF 36 kb)

ESM 3

S. Figure 3. Effect of vehicle treatment on PAI-1 signaling and downstream factors in 9 month and 18 month-old WT and APP/PS1 mice. Protein quantification by western blot was conducted, and t-PA, (A: * p= 0.0117, ** p= 0.0090) and PAI-1 (B: * p= 0.0231, WT 9mo vs WT 18mo ** p=0.0013, APP/PS1 9mo vs APP/PS1 18 mo ** p= 0.0042, ***p = 0.0003) in untreated WT and APP/PS1 groups were determined. Data are presented as Mean±SEM, n=5-7. (PDF 86 kb)

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Rodriguez, G., Eren, M., Haupfear, I. et al. Pharmacological inhibition of plasminogen activator inhibitor-1 prevents memory deficits and reduces neuropathology in APP/PS1 mice. Psychopharmacology 240, 2641–2655 (2023). https://doi.org/10.1007/s00213-023-06459-8

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