ACTIVITY-DEPENDENT REGULATION OF AMYLOID PRECURSOR PROTEIN (APP) BY POLO-LIKE KINASE 2 (PLK2): NOVEL ROLES IN SYNAPTIC PLASTICITY

Abstract

The brain uses a special feature, synaptic plasticity, for learning and memory. As forms of synaptic plasticity, associative plasticity, long-term potentiation (LTP) and long-term depression (LTD), is a positive feedback mechanism for memory encoding, whereas homeostatic plasticity (HSP) is a tuning process to stabilize neural networks. The synaptic plasticity is impaired in neurodegenerative disorders, including Alzheimer disease (AD). AD demonstrates pathological hallmarks, neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid β (Aβ) which is a proteolytic fragment of the amyloid precursor protein (APP). While APP expression facilitates synaptic formation and transmission, APP processing by synaptic activity and APP knock-out contribute to synaptic depression, suggesting APP involvement in synaptic plasticity. However, the physiological roles of APP and APP processing are not well understood.

Herein, we identify novel functions of APP and APP processing in synaptic plasticity and suggest their contribution to memory and AD pathogenesis. In heightened synaptic activity, Polo-like kinase 2 (Plk2), a homeostatic repressor of overexcitation, phosphorylates T668 and S675 of APP and promotes APP β-processing. Plk2 levels in brains of AD mouse models and patients are elevated in both a spatial and temporal manner. Genetic blockade of Plk2 kinase function prevents plaque deposits and activity-dependent Aβ production, and pharmacological inhibition hinders Aβ formation, synapse loss, and memory decline in AD mouse models. Furthermore, APP phosphorylation at T668 and S675 by Plk2 promotes GluA2 endocytosis in HSP. On the other hand, blocking phosphorylation of S655 and T686 inhibits GluA2 internalization in NMDAR-LTD. The synaptic connection between APP and GluA2 appears to occur via N-ethylmaleimide-sensitive factor (NSF).

Overall, Plk2-mediated Aβ production links synaptic overactivity to APP β-processing and synaptic depression; this process supports a physiological role for Plk2 as a homeostatic modulator. Pathological conditions in AD, however, disturb this homeostatic balance and increase Aβ production by Plk2. Moreover, regulation of GluA2-containing AMPAR trafficking by exclusive dual phosphosites of APP in HSP and LTD implicates a role for APP in the cellular mechanisms underlying learning and memory. Thus, alterations in APP phosphorylation or related kinases may have effects on cognitive processes in the brains.