Journal of Investigative Medicine:
EB Symposium Manuscript
Regulation of Cerebral Cholesterol Metabolism in Alzheimer Disease
Reiss, Allison B. MD; Voloshyna, Iryna PhD
From the Winthrop Research Institute, Department of Medicine, Winthrop University Hospital, Mineola, NY.
Received October 19, 2011, and in revised form December 14, 2011.
Accepted for publication December 14, 2011.
Reprints: Allison B. Reiss, MD, Department of Medicine, Winthrop University Hospital, 222 Station Plaza, North, Suite 502, Mineola, NY 11501. E-mail: AReiss@winthrop.org.
Supported by a grant from the Neuroscience Education and Research Foundation and an Innovative Research Grant from the Arthritis Foundation. Supported in part by a grant from the National Center for Research Resources (R13 RR023236).
Abstract: Alzheimer disease (AD) is an age-related neurodegenerative disorder that manifests as a progressive loss of memory and deterioration of higher cognitive functions. Alzheimer disease is characterized by accumulation in the brain of the β-amyloid peptide generated by β- and γ-secretase processing of amyloid precursor protein. Epidemiological studies have linked elevated plasma cholesterol and lipoprotein levels in midlife with AD development. Cholesterol-fed animal models exhibit neuropathologic features of AD including accumulation of β-amyloid peptide. Specific isoforms of the cholesterol transporter apolipoprotein E are associated with susceptibility to AD. Although multiple lines of evidence indicate a role for cholesterol in AD, the exact impact and mechanisms involved remain largely unknown. This review summarizes the current state of our knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in vitro and in vivo.
Alzheimer disease (AD), the most common form of dementia, is a slowly progressive neurodegenerative disease clinically characterized by memory impairment and pathologically characterized by the formation of extracellular senile plaques containing amyloid beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau protein in the brain.1 Substantial synaptic and neuronal loss occurs in critical brain areas, especially in cholinergic neurons in the basal forebrain region, with cortical shrinkage being predominant.2,3 Ultimately, the disease spreads throughout the cerebral cortex. In addition to memory deficits, patients with AD also experience visuospatial dysfunction, degradation of language, and a decline in their ability to carry out activities of daily living. Changes in mood and affect often accompany or precede memory decline. Alzheimer disease is a major public health problem owing to increasing prevalence, prolonged course, challenges to caregivers, and high expenditures for care.4,5
Although multiple lines of evidence indicate a role for cholesterol in AD, the exact impact and mechanisms involved remain largely unknown.6–8 This review summarizes the current state of our knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in animal, human, and cell culture systems.
THE AMYLOID HYPOTHESIS
Amyloid beta, the major peptide constituent of senile plaques, accumulates in the brain several decades before the disease is evident.9 The presence of Aβ plaques in the brain is a central neuropathologic feature of AD.10 Amyloid beta is formed by the sequential cleavage of its parent protein, the amyloid precursor protein (APP), a type I transmembrane protein with a large extracellular domain and a short cytoplasmic region (Fig. 1). Amyloid precursor protein can undergo proteolytic processing via either of 2 different pathways, one of which is amyloidogenic, whereas the other is not.11 In the amyloid-forming pathway, APP is acted upon first by the aspartyl protease β-site APP-cleaving enzyme-1 (BACE-1).12 β-site APP-cleaving enzyme-1 within the trans-Golgi network and early endosomes cuts APP 99 amino acids from the C-terminal to generate a soluble N-terminal fragment (APPsβ) and a membrane-bound 12-kd C-terminal fragment. Then, the γ-secretase releases pathogenic Aβ from the lipid bilayer in a process known as regulated intramembrane proteolysis.13,14 Inhibition of either of these secretases can block Aβ generation.15 Depending on the site of γ-secretase cleavage, 2 major forms of Aβ are generated, the 40-amino acid Aβ40, and the 42-amino acid Aβ42. The Aβ42 is the predominant species of Aβ in senile plaques.16,17 Once amyloid forms, a cascade is initiated, resulting in additional intracellular aggregations of the tau protein, which then form tangles. The nonamyloidogenic processing pathway involves the cleavage of APP at the Lys16-Leu17 bond within the Aβ peptide sequence and thus precludes Aβ formation.18
Approaches to AD treatment are under development. Strategies focus on preventing or reversing Aβ formation by influencing APP processing through manipulation of secretase expression/activity. Other disease-modifying therapies might inhibit Aβ aggregation or boost Aβ clearance.19
Cholesterol is an essential constituent of eukaryotic membranes that regulates lipid bilayer dynamics and structure and determines membrane biophysical properties.20 Tight regulation of brain cholesterol homeostasis is necessary to maintain neurological function.21 Nearly all cholesterol present in the brain is synthesized within the central nervous system (CNS), and its metabolism is regulated independently of that in peripheral tissues.22,23 An intact blood-brain barrier (BBB) prevents transport of cholesterol from peripheral circulation to the brain.24 Lipoproteins in human, mouse, and rat do not cross the BBB. The major sterol in the adult human brain is unesterified cholesterol, with small amounts of desmosterol and cholesteryl ester also detected.25 Brain cholesterol turnover is slow, with a half-life in humans of approximately 1 year.26
Neurons do not efficiently synthesize cholesterol and rely on astrocytes as an external source important for neuronal development and remodeling.27 It has been proposed that lipoproteins from glial cells are taken up by axons of neighboring neurons.28
Epidemiological observations have identified midlife hypercholesterolemia, but not later-life cholesterol elevation, as a major risk factor for AD.29,30 A study that followed 9844 members of the Kaiser Permanente Northern California Medical Group ages 40 to 45 who had blood work done between 1964 and 1973 found that even borderline elevations in cholesterol (> 220 mg/dL) increased the risk of developing AD 3 decades later.31 In contrast, The Prospective Population Study of Women conducted in Sweden starting in 1968–1969 with 1462 women without dementia aged 38 to 60 years found that a higher cholesterol level in 1968 was not associated with an increased risk of AD in 2000–2001.32
Some early epidemiological studies suggested that subjects who take statins, drugs that reduce plasma cholesterol by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, exhibit reduced susceptibility to AD.30,33,34 Statins are well characterized and tolerated and are the most prescribed lipid-lowering medications (Fig. 2).35 They are efficacious in decreasing cholesterol levels and also exert beneficial anti-inflammatory, antiplatelet aggregatory and antioxidant effects that are “pleiotropic” and unrelated to lipid lowering.36 In addition to cholesterol, downstream products of the mevalonate pathway include key isoprenoid intermediates. By inhibiting L-mevalonic acid synthesis, statins also block the production of these isoprenoids. Some of the cholesterol-independent effects of statins may be due to decreased prenylation of proteins involved in signal transduction in cells, particularly Rho and Rab family GTPases.37 In cultured neurons, statin inhibition of protein isoprenylation decreases Aβ secretion.38 Statins differ in their biochemical properties and particularly in BBB permeability. Some statins such as simvastatin and lovastatin are lipophilic and are able to cross the BBB even if it is intact. Rosuvastatin and pravastatin are more hydrophilic. Thus, statins are not considered to be therapeutically interchangeable. Because cholesterol is vital to normal brain function, there has been concern that more lipophilic statins may decrease cognitive function by lowering cholesterol in neuronal membranes.39
Based on the relationship between cholesterol and AD and inflammation and AD, statins were thought to hold promise, but conflicting data continue to accumulate with a number of studies failing to find a positive impact.40–42 Recently, in a Rotterdam study, a prospective evaluation of AD incidence in almost 7000 persons, use of statins, but not of nonstatin cholesterol-lowering drugs, was associated with a lower risk of AD.43
Cholesterol homeostasis is closely linked to multiple aspects of Aβ biology. Studies have shown that the cholesterol level influences the production of the pathogenic Aβ peptide. In 1998, Simons et al.44 showed in rat hippocampal neurons infected with recombinant Semliki Forest virus–carrying APP that reducing cellular cholesterol content decreased formation of Aβ. Cells were depleted of approximately 70% of their cholesterol content using a combination of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor lovastatin with the cholesterol-sequestering agent methyl-β-cyclodextrin.
Using lovastatin, Frears et al.45 lowered the cholesterol levels in 293 human cells transfected with a gene coding for APP under the control of a cytomegalovirus promoter. The lovastatin treatment markedly inhibited β-secretase cleavage. Supplementing the APP-transfected cells with cholesterol increased secretion of both Aβ40 and Aβ42.
Cholesterol binds to both APP and Aβ.46,47 Amyloid precursor protein binds to cholesterol specifically through its C-terminal transmembrane domain. Cholesterol has also been shown to directly modulate the processing of APP in neuronal cell cultures. Ehehalt et al.48 found that BACE-1 activity in mouse neuroblastoma N2a cells depends on intact lipid rafts and cholesterol- and sphingolipid-enriched microdomains within cellular membranes. Lipid rafts may thus act as surface catalysts, fostering the aggregation of Aβ. On the other hand, α-secretase is believed to reside primarily in the nonraft phase of the plasma membrane. The Ehehalt group hypothesized that cholesterol depletion shifts the partitioning of APP from lipid rafts to the lipid bilayer, leading to increased nonamyloidogenic α-cleavage.
In multiple animal models, elevated dietary cholesterol has been shown to increase amyloid plaque formation (Fig. 2). In an Aβ-depositing double transgenic (APP-presenilin) mouse model, consumption of a high cholesterol diet for 7 weeks elevated Aβ levels in the CNS.49 Cholesterol colocalizes with fibrillar Aβ in the amyloid plaques of transgenic mice.50 In transgenic mice, a typical Western diet containing 1% cholesterol consumed between ages 6 and 18 months increased Aβ accumulation and plaque burden, particularly in the dentate gyrus of the hippocampus.51 Fitz et al.52 fed a high-cholesterol diet to APP23 mice that overexpress human APP751 (familial Swedish AD mutant) for a 4-month period. This resulted in significantly worse memory deficits than in the same mouse model fed a normal diet.
Studies using New Zealand white rabbits have demonstrated that diet-induced hypercholesterolemia causes a 2-fold increase in brain Aβ concentration in the hippocampal cortex.53 The Aβ accumulation seen in cholesterol-fed rabbits can include senile plaquelike structures in the hippocampus and temporal lobe. In addition to increasing Aβ, cholesterol-enriched diets increase tau phosphorylation and oxidative stress in rabbit brains.54–56
A study in guinea pigs showed that lowering whole body cholesterol with statins decreased cerebral Aβ formation.57
Apolipoprotein E (ApoE) is a 35-kd, 299-amino acid glycoprotein and a major apolipoprotein in the CNS. It is responsible for transport of cholesterol between cells in the brain and the best-known bona fide genetic risk factor in sporadic AD.58 The ApoE gene is localized on chromosome 19. Humans express 3 naturally occurring variants of ApoE, differing by a single amino acid at either position 112 or 158: E2 (Cys112/Cys158), E3 (Cys112/Arg158), and E4 (Arg112/Arg158).59 ApoE3 is the most common allele. The ApoE2 allele reduces the risk of AD, whereas the ApoE4 allele dose dependently increases AD risk. Individuals homozygous for the E4 allele have a 50% to 90% chance of developing AD by age 85 years, and heterozygotes with 1 copy of E4 have an approximately 45% chance. Carriers of ApoE4 manifest dementia symptoms earlier than non-carriers with the disease and convert from mild cognitive impairment to AD at an accelerated rate.60 Murine studies have shown that, astrocytes and microglia are the primary ApoE secreting cells in the brain, but neurons can express ApoE under conditions of excitotoxic injury.61
The mechanisms by which ApoE isoforms affect risk of AD are uncertain. ApoE is found in the amyloid plaques of AD in humans.62,63 ApoE promotes the formation of Aβ fibrils in vitro and in transgenic mice with mutated APP (Fig. 2), more fibrillar Aβ deposits form in mice that express ApoE4 compared with ApoE3.64,65 In transgenic AD mouse models, a striking reduction in amyloid deposits is observed when the mice are ApoE-null.66 It has been postulated that ApoE functions as a chaperone for Aβ and that it regulates its conversion from a mixed random coil/α-helix to a β-sheet amyloid conformation.67 It has also been suggested that in AD patients with ApoE4, a decreased ability to clear Aβ contributes to increased Aβ accumulation and amyloid plaque formation.68
To maintain cholesterol homeostasis in the brain, a mechanism is required for efflux through the BBB into the circulation. This is accomplished through conversion of cholesterol to the relatively polar 24S-hydroxycholesterol, also called cerebrosterol, in a reaction catalyzed by the microsomal cytochrome P450 enzyme cholesterol 24-hydroxylase (CYP46A1).69 Cholesterol 24-hydroxylase is almost exclusively located in the brain, and the brain is the source of more than 90% of plasma 24-hydroxycholesterol.70 Cytochrome P450 enzyme cholesterol 24-hydroxylase is expressed in neurons of the brain but not the spinal cord, and not in myelin-producing cell types (oligodendrocytes) or in support cell types such as astrocytes.71 Approximately 6 to 7 mg of cholesterol crosses the BBB and leaves the human brain each day after conversion to 24S-hydroxycholesterol.72 Approximately 60% of cholesterol clearance from the brain occurs in the form of 24S-hydroxycholesterol. To a lesser extent, cholesterol is oxidized to 27-hydroxycholesterol in the brain by cholesterol 27-hydroxylase (CYP27A1), an enzyme found in the brain, and also in many other organs and tissues.73–75 In healthy male volunteers, Heverin et al.76 found that the 27-hydroxycholesterol concentration was higher in brachial artery blood than in blood taken from the internal jugular vein, indicating a significant net uptake of 27-hydroxycholesterol from the circulation into the brain, corresponding to 4 to 5 mg/d.76 Under conditions of elevated serum cholesterol, flux of 27-hydroxycholesterol into the brain is increased. 27-Hydroxycholesterol is taken up from the blood, acting as an important link between extracerebral and intracerebral pools of cholesterol, and may contribute to negative effects of hypercholesterolemia in the brain.76–78
A number of studies indicate that oxysterols affect the amyloid cascade. In rat primary cortical neurons, both 24S-hydroxycholesterol and 27-hydroxycholesterol are potent inhibitors of Aβ secretion (Fig. 2), but 24S-hydroxycholesterol is approximately 1000 times more potent.79 In primary human neurons isolated from brain tissue, treatment with 10-μmol/L 27-hydroxycholesterol for 24 hours reduced the level of Aβ peptides detected by Western blot in culture supernatants by 65%.80
Other studies have indicated that oxysterols may cause changes that favor AD development. In human neuroblastoma SH-SY5Y cells, treatment with 5-, 10-, and 25-μmol/L 24-hydroxycholesterol for 24 hours did not significantly alter secreted Aβ42 levels, whereas treatment with 5-, 10-, or 25-μmol/L 27-hydroxycholesterol substantially increased Aβ42 levels, possibly by elevating APP and BACE-1. In this study, 24-hydroxycholesterol favored APP processing via the nonamyloidogenic pathway that precludes generation of Aβ42. None of the treatments affected Aβ40 production.81
Halford and Russell82 cross-bred CYP46A1 knockout mice with an AD mouse model (APP-presenilin transgenic mice) and found that 24-hydroxylase deficiency did not impact formation of amyloid plaque in the brain, although it was associated with increased longevity in both male and female mice with AD. As seen previously, the rate of cholesterol turnover was diminished in the brains of mice lacking the 24-hydroxylase and, to maintain a steady state, cholesterol synthesis was reduced as a compensatory mechanism.83 Cholesterol synthesis in the liver was unaffected. When oxysterols exit the brain, they are metabolized in the liver to form bile acids or other water-soluble metabolites.
ABCA1 AND LXRS
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters constitute a group of evolutionary highly conserved cellular transmembrane proteins that transport a variety of macromolecules across biological membranes. Many ABC transporters, particularly in the A and G subfamilies, transport lipids such as sterols, phospholipids, and bile acids.84
Adenosine triphosphate–binding cassette transporter A1 (ABCA1) is a membrane-associated protein that transports cholesterol to high-density lipoproteins and mediates cellular cholesterol efflux.85,86 It is reported to be involved in ApoE metabolism and Aβ production in the CNS (Fig. 2).87–90 In particular, ABCA1 has been shown to modulate amyloid plaque formation and ApoE levels in the brain of Alzheimer transgenic mice (PDAPP murine model).5,88,89 Canepa et al.5 demonstrate a strong correlation between Aβ and ABCA1 levels. First, they observed that AD transgenic mice have reduced expression of ABCA1 in the brain. These findings were confirmed by in vitro experiments demonstrating that Aβ has an inhibitory effect on the expression of the cholesterol transporter ABCA1 in cultured astrocytes. Recent studies have shown that AD transgenic mice lacking ABCA1 develop increased Aβ levels and plaque pathology in the absence of changes in APP processing. Thus, Wahrle et al.,89 using PDAPP/ABCA-/- mice found that deletion of ABCA1 results in increased parenchymal Aβ levels, codeposition of poorly lipidated apoE with insoluble Aβ, and facilitation of amyloidogenesis. The PDAPP/ABC1 double transgenic mouse generated by Holtzman’s group overexpresses ABCA1. The ABCA1 level in these mice significantly modulated Aβ deposition.90 The striking phenotype that these mice possess is a complete absence of thioflavine-S–positive amyloid plaques, once again leading to the conclusion that increasing ABCA1 function may have a therapeutic effect on AD.
Liver X receptors (LXRs) are ligand-activated transcription factors that induce the expression of ApoE, ABCA1, and other genes of lipid metabolism. Liver X receptors act physiologically as cellular cholesterol sensors and are activated by oxysterols. The LXR-ABCA1-ApoE regulatory pathway is now considered a promising therapeutic target in AD.91–93 The therapeutic approach includes transcriptional regulation of ABCA1 levels by LXR agonists controlling lipidation, Aβ aggregation and amyloid clearance. However, the identification of proper LXR agonists in this regard is still in development in many research groups.93–95
Another ABC transporter, ABCA7, has been found to stimulate cellular cholesterol efflux to apoE-containing particles in the same way as ABCA1.96 ABCA7 reduces Aβ production in transfected cells not by altering the enzyme activities of APP secretase enzymes but by retaining APP in a perinuclear location, thereby reducing the availability of APP for Aβ production.
Acyl-coenzyme A:cholesterol acyltransferase (ACAT) catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty-acyl-coenzyme A in nearly all mammalian cells.97 Acyl-coenzyme A:cholesterol acyltransferase is a membrane-associated enzyme that is primarily localized in the endoplasmic reticulum. Acyl-coenzyme A:cholesterol acyltransferase serves as a regulator of intracellular cholesterol homeostasis by modulating intracellular free cholesterol concentration. In view of the critical role of ACAT in lipid metabolism, Huttunen et al.98 used various cell- and animal-based models to show that inhibition of ACAT strongly reduces generation of Aβ and protects from amyloid pathology. In APP-overexpressing transgenic mice, they showed that 2 months of treatment with the ACAT inhibitor CP-113,818 decreased maturation of APP, attenuated Aβ formation, and reduced amyloid pathology.98,99
Multiple threads of evidence connect cholesterol and AD. Epidemiological studies suggest a positive correlation between hypercholesterolemia and increased risk of AD. High dietary intake of cholesterol results in hypercholesterolemia and enhances Aβ deposition in rabbit, mouse, and guinea pig brains.49,53,57 Statins inhibit cholesterol synthesis and decrease Aβ levels and AD pathology in several animal models of AD. However, human studies of statins show variable outcomes. More research is needed with particular attention to stage of AD at the initiation of statin therapy, hydrophilicity of chosen drug and pleiotropic effects.100
The lipid composition of neurons impacts trafficking and/or activity of membrane-associated proteins that determine Aβ levels, including APP, BACE-1, and presenilins. A major risk factor for AD is the E4 allelic variant of ApoE, a protein that regulates the redistribution and homeostasis of cholesterol within the brain. It has recently been reported that ApoE facilitates intracellular Aβ degradation by microglia via reduction of intracellular cholesterol levels.101
Effective therapy for AD is a major unmet medical need. Although there is no cure at present, some therapeutic drugs inhibiting acetylcholinesterase have been used to alleviate the disease symptoms and improve the quality of life for patients with AD.102,103 Currently, no disease-modifying or antiamyloid therapies are available. There is burgeoning interest in the development of therapeutics for prodromal AD. This is driven by the hypothesis that disease-modifying therapy is most likely to be efficacious in the earliest stages of the pathologic cascade of events leading to neuronal dysfunction and death. Current marketed therapies for AD offer palliative cognitive benefits with little to no impact on the underlying pathology, or on long-term disease progression. Effective treatments for AD that address the underlying disease may include antiamyloid antibodies to reduce Aβ in brain and neurotrophic factor drugs that enhance the neuroregenerative capacity of the brain.104,105 A new development linking a BACE-1 inhibitor to a cholesterol molecule enriches the expression of the inhibitor in lipid rafts, increasing its potency.106,107 It is hoped that this type of targeted therapy, now in its infancy, may have substantial impact on this debilitating illness.
In summary, although the exact function of cholesterol in the control of Aβ generation, aggregation, and toxicity remains unclear, there is substantial evidence that elevated cholesterol levels increase AD risk. Cholesterol-lowering strategies that decrease production (statins) or increase efflux (LXR agonists) are being explored as a means to reduce or remove Aβ, with the ultimate goal of slowing or preventing AD.
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Alzheimer disease; amyloid precursor protein; β-amyloid peptide; oxysterol; apolipoprotein E; ABCA1; LXR
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