Cholesterol involvement in the pathogenesis of neurodegenerative diseases

doi:10.1016/j.mcn.2009.07.013

Molecular and Cellular Neuroscience

Volume 43, Issue 1, January 2010, Pages 33-42

https://doi.org/10.1016/j.mcn.2009.07.013 Get rights and content

Abstract

Cholesterol, an essential component of cell membranes, plays an important role in the maintenance of cellular homeostasis and transmembrane communication within and between cellular compartments. In the brain that contains the highest levels of cholesterol in the body, cholesterol traffic occurs between nerve cells and between intracellular organelles in neurons to subserve normal brain function. Whereas glial cells produce the largest quantities of cholesterol, neurons also acquire cholesterol synthesized by astrocytes. The intracellular organelle endosomes and lysosomes receive and distribute cholesterol through the endocytic and retrograde transport pathways. However, deregulated cholesterol trafficking appears to be involved in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD) and Niemann–Pick disease type C (NPC) diseases. Under the pathological conditions of these neurodegenerative diseases, aberrant molecular interactions or particular depositions of cholesterol have been observed as critical causes to precipitate neuronal cell death. Here, we review the recent advances in terms of the role of cholesterol in healthy brain and molecular mechanisms of cholesterol involvement in AD, PD and NPC diseases. We discuss the different lines of evidence supporting different models of anomalous intracellular cholesterol trafficking with emphasis on cholesterol interactions with α-synuclein, NPC1 and NPC2 in AD, PD and NPC.

Introduction

Cholesterol plays integral roles in cell structure and function. It is an essential component of the cell membranes required for membrane lipid organization. Different concentrations of cholesterol regulate membrane fluidity, and thereby structural integrity and functional specificity at various cellular locations. However, cholesterol moves within and between different membranes and intracellular organelles. Cytoplasmic cholesterol is also a source of bioactive molecules such as steroid hormones, vitamin D and bile acids. Thus, cholesterol is implicated in regulating diverse cellular metabolisms, compartmental homeostasis, and molecular interactions in extracellular and intracellular communication. As a polar lipid cholesterol is also toxic to its host cell, and when accumulated, it causes cell death. It is thus important that while cholesterol is required, it must be harnessed in certain forms, locations and concentrations. Extensive studies on cholesterol synthesis have been carried out in liver and vascular endothelial cells. In contrast, much remains to be understood about the role of cholesterol in normal brain function, and how the brain cells deal with high levels of cholesterol under various conditions including aging. Recently considerable evidence implicates cholesterol in the loss of nerve cells e.g. as demonstrated in the cholesterol transport disorder of Niemann–Pick disease type C (NPC). In this review, we discuss the general aspect of cholesterol distribution and function in the brain, and recent advances in our understanding of cholesterol involvement in Alzheimer's disease (AD), Parkinson's disease (PD) and NPC.

Section snippets

Cholesterol distribution and function in the brain

Brain contains the highest levels of cholesterol in mammalian bodies. The human brain contains as much as 25% of total body cholesterol and cholesterol derivatives (∼ 20 mg/g), although the human brain accounts for ∼ 2% of total body weight (Dietschy and Turley, 2004, Vaya and Schipper, 2007). In the mouse, the brain contains about 15% of total cholesterol (15 mg/g), from ∼ 8 mg/g in the grey matter to ∼ 40 mg/g in the spinal cord (Xie et al., 2003). The five-fold more cholesterol in the spinal

Cholesterol in Alzheimer's disease

Recent studies suggest that high-level cholesterol is a risk factor in CNS pathophysiology associated with the development of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) (reviewed in Simons and Ehehalt (2002) and Wustner et al. (2005)). Systematic meta-analyses of Alzheimer disease genetic association suggest that SOAT1 (the gene encoding Acyl-coenzyme A:cholesterol acyltransferase or ACAT) is associated with risk of AD and that a common polymorphism

Cholesterol in Parkinson's disease

It has been shown that body mass index is associated with risk of Parkinson's disease in a retrospective study of 272 men and 254 women with PD from study cohorts of 22,367 Finnish men and 23,439 women in 18.8 years (Hu et al., 2006). In another large prospective analysis, high dietary intake of cholesterol increases the risk of PD (Hu et al., 2008). At cellular and molecular levels, oxidative stress, inflammation and increased α-synuclein confer risk for development of

Niemann–Pick disease type C

Niemann–Pick disease encompasses a heterogeneous group of lysosomal lipid storage diseases with autosomal-recessive inheritance. Patients with type A have severe neural and visceral symptoms, and patients with type B have chronic visceral symptoms, due to mutations of sphingomyelinase and accumulation of acidic sphingomyelin in lysosomes. NPC is a subacute progressive neurodegenerative disorder, with cholesterol and sphingolipid accumulation in endosomes and lysosomes of neurons due to

Other function and interface of NPC1 and NPC2 pathway

Studies show that there is a defect in NPC neurons of cholesterol trafficking from the endogenous synthetic pathway to axons through the Golgi apparatus, but not from the plasma membrane endocytic pathway (Karten et al., 2003). Recently, NPC1 has been shown to reduce accumulation of axonal spheroids (Zhang et al., 2008). Additional to neuronal defects, there is also a loss of fibrillary astrocyte function in NPC, but enforced expression of NPC1 results in an astrocyte-specific rescue of the

Concluding remarks

Cholesterol transport in the brain involves trafficking between intracellular organelles in and between neurons and glial cells. Deregulation of cholesterol transport with increased cholesterol deposition in neurons is implicated not only in NPC but also AD and PD. α-Synuclein interacts with cholesterol rafts in its transport to nerve terminals, and the excess protein–lipid complex is a hallmark of PD. NPC1 and NPC2 may coordinate to transfer cholesterol from each other, while NPC1 is also

Acknowledgments

This work was supported by grants from the National Health and Medical Research Council of Australia, and Cancer Council of Victoria, Australia. Y.T. is a scholarship recipient of the Chinese Scholarship Council.

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ReviewCholesterol involvement in the pathogenesis of neurodegenerative diseases

Abstract

Introduction

Section snippets

Cholesterol distribution and function in the brain

Cholesterol in Alzheimer's disease

Cholesterol in Parkinson's disease

Niemann–Pick disease type C

Other function and interface of NPC1 and NPC2 pathway

Concluding remarks

Acknowledgments

Neurochem. Int.

Genomics

Biophys. J.

J. Lipid. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Lipid. Res.

J. Lipid. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Genet. Metab.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Mech. Ageing. Dev.

Neuron

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

Mol.Cell.Endocrinol.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

Lancet

Prog. Lipid Res.

Brain Res. Dev. Brain Res.

Mol. Cell

Neurosci. Lett.

Lancet. Neurol.

J. Biol. Chem.

FEBS. Lett.

Effects of the cholesterol-lowering compound methyl-beta-cyclodextrin in models of alpha-synucleinopathy

J. Neurochem.

Statins reduce neuronal alpha-synuclein aggregation in in vitro models of Parkinson's disease

J. Neurochem.

Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells

J. Cell. Biol.

Brain neutral lipids mass is increased in alpha-synuclein gene-ablated mice

J. Neurochem.

Cholesterol accumulation and liver cell death in mice with Niemann–Pick type C disease

Hepatology

Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database

Nat. Genet.

Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain

J. Int. Med.

Brain cholesterol: long secret life behind a barrier

Arterioscler. Thromb. Vasc. Biol.

Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann–Pick type C disease

Hum. Mol. Genet.

Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization

Nat. Chem. Biol.

Review
Cholesterol involvement in the pathogenesis of neurodegenerative diseases