The translational potential of cholesterol-based therapies for neurological disease

Metabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders

“…Cholesterol levels are tightly regulated by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor for genes involved in cholesterol synthesis ( Brown and Goldstein, 2009 ). RNA profiling of mouse and human brain astrocytes, both through bulk sequencing ( Zhang et al, 2014 , 2016 ; Chai et al, 2017 ) and single-cell sequencing ( Batiuk et al, 2020 ; Endo et al, 2022 ), has revealed high expression levels of SREBP2 and 12 other genes involved in cholesterol biosynthesis in developing astrocytes ( Pfrieger and Ungerer, 2011 ; Valenza et al, 2023 ). This suggests a significant role for astrocytes in cholesterol production and metabolism.…”

The associations between peripheral inflammatory and lipid parameters, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events

“…Several studies have shown that cholesterol levels in the central nervous system are closely related to cognitive function [ 9 , 10 ]. On one hand, the close association between cholesterol and various aspects of brain function, such as cytotropic support, neuronal activity, and neural information transmission, highlights its significance as a crucial component of neurons [ 11 , 12 ]. However, on the other hand, cholesterol abnormalities are also implicated in the development of atherosclerosis, chronic neuroinflammatory responses, and endothelial cell dysfunction, thereby serving as a risk factor for CVD.…”

Brain cholesterol therapy for Huntington's disease – Does it make sense?

“…Over the last 25 years, work in the Cattaneo lab has demonstrated across a wide variety of models that cholesterol biosynthesis is severely reduced in the HD brain. 2 A meta‐analysis of all the cognitive data from studies on HD mice exposed to cholesterol‐increasing strategies in the brain also showed that, regardless of the approach type, delivery system, mouse genotype and time of administration, the cognitive performance of treated HD mice greatly improved relative to untreated HD groups. 2 , 3 As such, the concept of increasing cholesterol levels or stimulating its biosynthesis in the HD brain is well justified.…”

“…Various strategies have been explored to raise cholesterol levels in the HD mouse brain. 2 Direct infusion into the brain of 369 µg of cholesterol via an osmotic‐minipump rescued both motor and cognitive abnormalities, while 15 µg improved cognition only. A gene therapy approach forcing expression of the SREBP2 gene (the transcription factor promoting cholesterol biosynthesis) in astrocytes, again, leads to a rescue of cognitive and motor functions in HD mice.…”

“…Neurons have limited cholesterol biosynthesis capabilities and rely on astrocytes for their cholesterol supply, so as to protect them from the potentially harmful effects of excessive cholesterol production. Over the last 25 years, work in the Cattaneo lab has demonstrated across a wide variety of models that cholesterol biosynthesis is severely reduced in the HD brain 2 . A meta‐analysis of all the cognitive data from studies on HD mice exposed to cholesterol‐increasing strategies in the brain also showed that, regardless of the approach type, delivery system, mouse genotype and time of administration, the cognitive performance of treated HD mice greatly improved relative to untreated HD groups 2,3 .…”