The emerging role of polo-like kinase 2 in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau tangles. Protein phosphorylation is increasingly recognized as a key modulator of AD pathology, but the specific kinases involved remain incompletely characterized. Polo-like kinase 2 (PLK2), a serine/threonine kinase previously studied in Parkinson's disease, has recently emerged as a potential contributor to AD pathogenesis. This review explores the physiological and pathological roles of PLK2, emphasizing its expression in the brain, its regulation by neuronal activity, and its involvement in synaptic homeostasis. Evidence from postmortem brain studies, in vivo models, and cell-based experiments indicates that PLK2 is associated with AD through multiple mechanisms. PLK2 has been shown to modulate the amyloidogenic processing of amyloid precursor protein (APP), is associated with increased Aβ production, and can directly phosphorylates APP at critical sites. Elevated PLK2 levels have also been associated with reduced APP surface expression and increased endocytosis, changes that are consistent with enhanced Aβ generation. Although direct phosphorylation of Tau by PLK2 has not been clearly established, recent findings suggest that PLK2 activity can modulate Tau protein levels and influence its phosphorylation state, potentially through regulation of other kinases and phosphatases. Pharmacological inhibition of PLK2 has shown promising effects in transgenic mouse models of AD, including modulation of Aβ and Tau pathology and improvement in cognitive performance, with some sex-specific responses. While these findings support a contributory role for PLK2 in AD-relevant pathways, its precise position within the causal hierarchy of disease progression remains to be fully established.