I029 The type ii diabetes medication metformin rescues cognitive deficits in a mouse model of Huntington’s disease

<h3>Background</h3> Huntington’s Disease (HD) is a fatal progressive neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (HTT) gene. In HD, progressive cognitive impairments often precede the onset of classical motor symptoms. Metformin intake has been associated with better cognitive function in the Enroll-HD database,¹ however this has not been confirmed in preclinical models. <h3>Aims</h3> To evaluate whether metformin can modify the cognitive phenotype of the YAC128 mouse and to explore the mechanism through which metformin exerts its effect. <h3>Methods</h3> Yac128 mice were treated with metformin (2mg/mL) ad libitum in drinking water. The attentional set-shifting and novel object tests were used to assess cognitive symptoms. LC-MS/MS proteomic analysis was performed on striatal and cortical tissues. <h3>Results</h3> YAC128 mice show an increased number of errors in extra dimensional set-shifting (EDS, a task assessing attentional switching). Metformin completely reversed the number of EDS errors made. Metformin also improved recognition memory on the novel object test. Proteomic analyses revealed significant changes in protein expression in both the striatum and medial prefrontal cortex of the Yac128 mice and metformin was shown to reverse many of these protein changes. Pathway enrichment analysis indicates that metformin acts by improving synaptic plasticity, energy metabolism and ribosomal translation. <h3>Conclusions</h3> Together these findings confirm a deficit in executive function in the YAC128 mouse model of HD which can be rescued by metformin. Proteomic analysis gives insights into the mechanism of action. Our data supports metformin as a potential therapeutic for cognitive decline in HD. <h3>Reference</h3> Hervás D, Fornés-Ferrer V, Gómez-Escribano AP, Sequedo MD, Peiró C, Millán JM, <i>et al</i>. Metformin intake associates with better cognitive function in patients with Huntington’s disease. <i>PLOS ONE</i>. 2017;<b>12</b>(6):e0179283.