Inhibition of PLK2 activity affects APP and tau pathology and improves synaptic content in a sex-dependent manner in a 3xTg mouse model of Alzheimer's disease

Autor: Laura Martínez-Drudis, Razan Sheta, Rémi Pellegrinato, Salma Loukili, Cyntia Tremblay, Frédéric Calon, Serge Rivest, Abid Oueslati
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Neurobiology of Disease, Vol 172, Iss , Pp 105833- (2022)
Druh dokumentu: article
ISSN: 1095-953X
96240318
DOI: 10.1016/j.nbd.2022.105833
Popis: Converging lines of evidence suggest that abnormal accumulation of the kinase Polo-like kinase 2 (PLK2) might play a role in the pathogenesis of Alzheimer's disease (AD), possibly through its role in regulating the amyloid β (Aβ) cascade. In the present study, we investigated the effect of inhibiting PLK2 kinase activity in in vitro and in vivo models of AD neuropathology. First, we confirmed that PLK2 overexpression modulated APP and Tau protein levels and phosphorylation in cell culture, in a kinase activity dependent manner. Furthermore, a transient treatment of triple transgenic mouse model of AD (3xTg-AD) with a potent and specific PLK2 pharmacological inhibitor (PLK2i #37) reduced some neuropathological aspects in a sex-dependent manner. In 3xTg-AD males, treatment with PLK2i #37 led to lower Tau burden, higher synaptic protein content, and prevented learning and memory deficits. In contrast, treated females showed an exacerbation of Tau pathology, associated with a reduction in amyloid plaque accumulation. Overall, our findings suggest that PLK2 inhibition alters key components of AD neuropathology in a sex-dependent manner and might display a therapeutic potential for the treatment for AD and related dementia.
Databáze: Directory of Open Access Journals
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