Dysregulated Brain Cholesterol Metabolism Is Linked to Neuroinflammation in Huntington's Disease

Abstract

Huntington's disease is an autosomal‐dominant, neurodegenerative disorder caused by a CAG repeat expansion in exon‐1 of the huntingtin gene. Alterations in cholesterol metabolism and distribution have been reported in Huntington's disease, including abnormal interactions between mutant huntingtin and sterol regulatory element‐binding proteins, decreased levels of apolipoprotein E/cholesterol/low‐density lipoprotein receptor complexes, and alterations in the synthesis of ATP‐binding cassette transporter A1. Plasma levels of 24S‐hydroxycholestrol, a key intermediary in cholesterol metabolism and a possible marker in neurodegenerative diseases, decreased proportionally to the degree of caudate nucleus atrophy. The interaction of mutant huntingtin with sterol regulatory element‐binding proteins is of particular interest given that sterol regulatory element‐binding proteins play a dual role: They take part in lipid and cholesterol metabolism, but also in the inflammatory response that induces immune cell migration as well as toxic effects, particularly in astrocytes. This work summarizes current evidence on the metabolic and immune implications of sterol regulatory element‐binding protein dysregulation in Huntington's disease, highlighting the potential use of drugs that modulate these alterations. © 2020 International Parkinson and Movement Disorder Society

Lovastatin Differentially Regulates α7 and α4 Neuronal Nicotinic Acetylcholine Receptor Levels in Rat Hippocampal Neurons

“…It has been speculated that this loss underlies neuronal dysfunctions and the cognitive deficits present at this stage of life [ 41 , 42 , 43 ]. It has also been surmised that dysregulation of cholesterol metabolism is a major factor in neurological diseases accompanied by cognitive dysfunction, such as Alzheimer disease [ 44 , 45 ] (reviewed in [ 23 ]), Parkinson disease [ 46 ], and Huntington disease [ 47 ]. Epidemiological studies have suggested that individuals treated with statins have a lower risk of developing Alzheimer disease [ 25 , 28 , 48 ].…”

The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

“…57 Cholesterol homeostasis and neuroinflammatory signaling are connected in neurodegeneration. 179 Indeed, Npc1 −/− mice displayed dysregulated expression of inflammatory mediators. 180 Hypercholesterolemia produces microglial activation, and high-cholesterol diet promotes inflammatory responses.…”

“…Cholesterol homeostasis and neuroinflammatory signaling are connected in neurodegeneration 179 . Indeed, Npc1 −/− mice displayed dysregulated expression of inflammatory mediators 180 .…”

The Involvement of Lactosylceramide in Central Nervous System Inflammation Related to Neurodegenerative Disease

“…Their main functions include supporting, nourishing, and creating a suitable microenvironment for neuron survival ( Sofroniew and Vinters, 2010 ; Colombo and Farina, 2016 ). When astrocytes are activated to enter a pro-inflammatory state ( Sofroniew, 2014 ), the produced pro-inflammatory factors, chemokines, reactive oxygen species, and secondary messengers work together to induce neuroinflammation, resulting in multifaceted dysfunction, including but not limited to abnormal autophagy ( Bosch and Kielian, 2015 ; Thangaraj et al, 2020 ), lipid metabolism disorders ( Gonzalez-Guevara et al, 2020 ), energy supply disorders ( Trudler et al, 2015 ), and other abnormalities of cell physiology, which ultimately destroys neurons and synaptic function. At the same time, neuroinflammation hinders cell and tissue repair and regeneration, resulting in the irreversibility of neurodegeneration ( Schain and Kreisl, 2017 ).…”