Role of lipid phosphatase in brain insulin resistance related to neuroprotection and memory function

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Although brain insulin resistance is a cause of cognitive impairment associated with type 2 diabetes and Alzheimer's disease, the precise underlying mechanism is largely unknown. In the present study, we found that lipid phosphatase SHIP2, a negative regulator of insulin signaling, is increased in the brain of type 2 diabetic db/db and aged mice. Mice overexpressing SHIP2 exhibited impaired memory performance with disrupted insulin signaling and increased apoptosis in the brain. Importantly, inhibition of SHIP2 ameliorated the impairment of hippocampal synaptic plasticity and memory formation in db/db mice. These results suggest that inhibition of SHIP2 is a novel therapeutic approach in brain dysfunction related to insulin resistance with type 2 diabetes.