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

Abstract

In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyteneuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. Huntington's disease (HD) is an adult-onset neurodegenerative disorder characterized by cell loss mainly in the striatum and cortex. Its pathophysiology is linked to an expanded CAG repeat in the IT-15 gene, which leads to an elongated polyQ tract in huntingtin (HTT) protein. No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 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). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.In adulthood, astrocytes produce cholesterol, which is secreted as a complex with apolipoprotein (apo) E lipoproteins and delivered to neurons. 11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 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 neur...

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

“…Whereas some evidence points to dramatic downregulation of cholesterol in the brain [22, 44, 45], there also is evidence that, in spite of progressive reduction of brain cholesterol biosynthesis, steady-state levels of total cholesterol remain constant, suggesting compensatory mechanisms [21]. In support, a recent study reported that at least one precursor in the Bloch cholesterol synthetic pathway (desmosterol) is increased in R6/1 mice [31], thus supporting compensatory mechanisms to keep steady levels of cholesterol.…”

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

“…It is, for instance, known from the interactions of immune cells that inflammatory reactions may be dramatically boosted in feed-forward loops, and that they can therefore not be predicted from reactions of individual cells (Gantner et al 1996). Something similar may apply to the cycle of activated astrocytes affecting neurons and stressed neurons further activating astrocytes (Valenza et al 2015;Volterra and Meldolesi 2005).…”

“…More recent research has shown that also non-neuronal cells may play a role in neurodegeneration. For instance, genetic or non-genetic alterations in astroglial cells may adversely affect the survival of neurons in models of human diseases related to the RETT syndrome, Huntington's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis (Gallardo et al 2014;Kohutnicka et al 1998;Lukovic et al 2015;Mayo et al 2014;Valenza et al 2015;Williams et al 2014).…”

“…There is genetic evidence that astrocytes can contribute to neuropathology, e.g., in the RETT syndrome (Lioy et al 2011;Williams et al 2014), amyotrophic lateral sclerosis (ALS) (Nagai et al 2007), or Huntington's disease (Valenza et al 2015). However, for most other situations, the role of these cells, as bystander or aggressor, is less understood.…”

“Targeting astrocytes in CNS injury and disease: A translational research approach”

“…Inhibition of astrocyte-mediated inflammatory signaling through TNFα enhanced motor function and reduced aggregates of mutant huntington in a mouse model of HD, suggesting anti-inflammatory treatments may help slow the progression of HD (Hsiao et al, 2014). Recent findings report that cholesterol biosynthesis by astrocytes is reduced in HD, leading to neuronal deficits (Valenza et al, 2015). Additionally, accumulation of huntington aggregates in astrocytes reduced astrocytes secretion of brain derived neurotrophic factor (BDNF) (Wang et al, 2012).…”