RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly, with limited effective treatments available in clinical practice. Impaired glucose metabolism has long been observed in the brains of AD patients, yet the mechanisms linking metabolic signals to AD pathogenesis remain elusive. Our previous study demonstrated that growth signals regulate genomic stability through RNF168 phosphorylation. Here, we report that phosphorylation of RNF168 at Ser60 is significantly elevated in the hippocampi of Aβ-based mouse models of AD. Genetic dephosphorylation of RNF168 S60 enhances DNA damage response, reduces double-strand breaks (DSBs), and ameliorates learning and memory deficits in Aβ-based mouse models of AD. Mechanistically, RNF168 S60 phosphorylation impairs long-term potentiation (LTP) of mossy fiber-CA3 synapses in the hippocampus. Importantly, genetic dephosphorylation of RNF168 S60 rescues the deficits in Mossy fiber-CA3 synapse LTP, AD-related spine loss and Aβ pathology. Pharmacological inhibition of RNF168 phosphorylation by S6K1 inhibitor PF-4,708,671 alleviated learning and memory deficits. Furthermore, we demonstrated that the anti-hyperglycemia drug metformin improved learning and memory by inhibiting RNF168 phosphorylation. Our findings provide a novel therapeutic target for addressing synaptic dysfunction in Alzheimer's disease.