Tissue-Plasminogen Activator Attenuates Alzheimer's Disease-Related Pathology Development in APPswe/PS1 Mice

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
Ayman ElaliSerge Rivest

Abstract

Alzheimer's disease (AD) is the leading cause of dementia among elderly population. AD is characterized by the accumulation of beta-amyloid (Aβ) peptides, which aggregate over time to form amyloid plaques in the brain. Reducing soluble Aβ levels and consequently amyloid plaques constitute an attractive therapeutic avenue to, at least, stabilize AD pathogenesis. The brain possesses several mechanisms involved in controlling cerebral Aβ levels, among which are the tissue-plasminogen activator (t-PA)/plasmin system and microglia. However, these mechanisms are impaired and ineffective in AD. Here we show that the systemic chronic administration of recombinant t-PA (Activase rt-PA) attenuates AD-related pathology in APPswe/PS1 transgenic mice by reducing cerebral Aβ levels and improving the cognitive function of treated mice. Interestingly, these effects do not appear to be mediated by rt-PA-induced plasmin and matrix metalloproteinases 2/9 activation. We observed that rt-PA essentially mediated a slight transient increase in the frequency of patrolling monocytes in the circulation and stimulated microglia in the brain to adopt a neuroprotective phenotype, both of which contribute to Aβ elimination. Our study unraveled a new role of...Continue Reading

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Citations

Mar 5, 2016·Frontiers in Aging Neuroscience·Ayman ElAli, Noëmie Jean LeBlanc
Jan 19, 2018·International Journal of Molecular Sciences·Marzena Wyganowska-ŚwiątkowskaJerzy Jankun
May 1, 2021·International Journal of Molecular Sciences·Manuel YepesCynthia Martin-Jimenez
Aug 4, 2021·Brain, Behavior, and Immunity·Mohammed A Al-OnaiziAyman ElAli

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