Inhibition of Polo-like kinase 2 ameliorates pathogenesis in Alzheimer's disease model mice

Abstract

Alzheimer disease (AD) is a neurodegenerative disorder characterized by pathological hallmarks of neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid beta (A beta), a cleavage fragment of amyloid precursor protein (APP). Enhanced neuronal activity and seizure events are frequently observed in AD, and elevated synaptic activity promotes A beta production. However, the mechanisms that link synaptic hyperactivity to APP processing and AD pathogenesis are not well understood. We previously found that Polo-like kinase 2 (Plk2), a homeostatic repressor of neuronal overexcitation, promotes APP beta-processing in vitro. Here, we report that Plk2 stimulates A beta production in vivo, and that Plk2 levels are elevated in a spatiotemporally regulated manner in brains of AD mouse models and human AD patients. Genetic disruption of Plk2 kinase function reduces plaque deposits and activity-dependent A beta production. Furthermore, pharmacological Plk2 inhibition hinders A beta formation, synapse loss, and memory decline in an AD mouse model. Thus, Plk2 links synaptic overactivity to APP beta-processing, A beta production, and disease-relevant phenotypes in vivo, suggesting that Plk2 may be a potential target for AD therapeutics.