Cholesterol (chol) in the brain is produced locally by astrocytes and used by neurons. Perturbation of its metabolism is linked to brain diseases. Data from the last 20 years have shown that activity of this pathway is reduced in the brain of 7 rodent models of Huntington's Disease (HD) and that reversing this brain defect through chol-raising strategies is beneficial. In a first strategy, we injected chol-laden brain-permeable nanoparticles (NPs) into the peritoneum of rapidly progressing R6/2 HD mice. NPs reached the brain, released chol and restored cognition (Valenza,EMM,2015). In the same mice, we used minipumps to deliver 3 increasing doses of chol directly into striatum and determined that the highest dose saved both motor and cognitive deficits while only cognition could be treated with the lower doses (Birolini,EMM,2020). A third strategy used gene therapy to increase chol biosynthesis through forced expression of SREBP2 -a key trigger of cholesterol biosynthesis- in striatal astrocytes, leading to reversal of HD phenotypes (Birolini,Brain,2021). In our new study (submitted), we used a recent formulation of brain-permeable NPs with increased chol loading capacity (Birolini,JCR, 2021), to explore the long-term therapeutic potential of chol administration to the brain of the slow-progressing zQ175DN HD mice. Pre-symptomatic or symptomatic treatment normalized cognitive behavior for up to 5 months (mo), and improved motor and neuropathological defects. Repeated treatment produced long-lasting benefits for 12 mo without serious side-effects. The distribution of data from the cognitive tests administered to HD mice treated with any of the treatments mentioned above, for a total of 381 mice (comprising wt, HD and HD-treated mice) showed that regardless of treatment, timing, and animal model, increased chol biosynthesis in the brain of HD mice is a therapeutically viable option against cognitive deficits, highlighting its translational potential in patients.