Cholesterol Defect Is Marked across Multiple Rodent Models of Huntington's Disease and Is Manifest in Astrocytes

Abstract

Brain cholesterol, which is synthesized locally, is a major component of myelin and cell membranes and participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, and synaptogenesis. Here we show that brain cholesterol biosynthesis is reduced in multiple transgenic and knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits in mutant astrocytes. Mice carrying a progressively increased number of CAG repeats show a more evident reduction in cholesterol biosynthesis. In postnatal life, the cholesterol-dependent activities of neurons mainly rely on the transport of cholesterol from astrocytes on ApoE-containing particles. Our data show that mRNA levels of cholesterol biosynthesis and efflux genes are severely reduced in primary HD astrocytes, along with impaired cellular production and secretion of ApoE. Consistently, in CSF of HD mice, ApoE is mostly associated with smaller lipoproteins, indicating reduced cholesterol transport on ApoE-containing lipoproteins circulating in the HD brain. These findings indicate that cholesterol defect is robustly marked in HD animals, implying that strategies aimed at selectively modulating brain cholesterol metabolism might be of therapeutic significance.

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

“…9,10,18,50 Additionally, synaptosomes carry suboptimal levels of sterols in early R6/2 model. 8 Here, we showed that a non-cell autonomous cholesterol-handling defect in astrocytes affects cholesterol shuttling between astrocytes and neurons, which has a reversible detrimental effect on synaptic-related parameters in HD neurons.…”

“…Quantitative assays confirmed that concentrations of apoE ( Figure 1e) and cholesterol ( Figure 1f) were significantly reduced in conditioned media from Q140/7 astrocytes and from primary R6/2 astrocytes compared with their respective controls. The impairment in apoE release is likely due to reduced synthesis of intracellular apoE as indicated by reduced mRNA and protein levels in YAC128 astrocytes 8 and in R6/2 and HD NS-derived astrocytes (Supplementary Figure 1g).…”

“…7 The effects on neurite outgrowth in HD neurons following the silencing or overexpression of active SREBP2 in astrocytes demonstrate a link between cholesterol synthesis in astrocytes and subsequent efflux likely under the regulating effect of oxysterols, such as 24OHC. 46 Reduced levels of 24OHC in HD [8][9][10] may therefore exacerbate cholesterol unbalance between astrocytes and neurons.…”

“…3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC).…”

“…15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neurons in HD. Reduced secretion of cholesterol bound to apoE lipoproteins by HD astrocytes negatively influenced neurite outgrowth and neuronal synaptic properties.…”