Deciphering Cholesterol efficacy on cognition in prodromal Huntington’s disease

Huntington’s disease (HD) is a rare, hereditary, degenerative disorder of the brain caused by a mutation in a single gene and characterized by motor, behavioral and cognitive disturbances, which appear in mid-adult life. After a variable pre-symptomatic period, individuals carry the HD mutation enter in a preclinical stage called “prodromal phase”. At this stage, subtle changes in cognition and behavior have been described even 10 years before motor symptoms begin. Although cognitive impairments begin many years before motor onset and are often reported as the most debilitating aspects of HD, there are no drugs or treatments that efficiently target these aspects.
One of the earliest dysfunctions identified in HD is related to cholesterol production within the brain. Brain cholesterol is separated by the periphery and its local production is critical for synaptic function.  In HD brain cholesterol production is early reduced contributing to affect the synaptic communication between neurons. Recently, strategies aimed at delivering cholesterol to the brain of HD mouse models have been demonstrated to prevent cognitive decline at prodromal phase, but the mechanisms of Cholesterol efficacy are still largely unexplored.
Here we want to identify the synaptic- and circuit-based changes underlying Cholesterol efficacy to prevent early cognitive deficits in prodromal HD mouse models. The identification of the first alterations in the synaptic machinery overlaying early cognitive decline will help to validate Cholesterol-based strategies as preventive therapeutic option for HD but also to identify new targets of intervention before the neurodegeneration starts.