Lipid metabolism in Alzheimer s and Parkinson s disease

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1 Future Lipidology ISSN: (Print) (Online) Journal homepage: Lipid metabolism in Alzheimer s and Parkinson s disease Qin Xu & Yadong Huang To cite this article: Qin Xu & Yadong Huang (2006) Lipid metabolism in Alzheimer s and Parkinson s disease, Future Lipidology, 1:4, To link to this article: Copyright 2006 Future Medicine Ltd Published online: 18 Jan Submit your article to this journal Article views: 59 View related articles Full Terms & Conditions of access and use can be found at

2 REVIEW Lipid metabolism in Alzheimer s and Parkinson s disease Qin Xu & Yadong Huang Author for correspondence Gladstone Institute of Neurological Disease, USA and, Gladstone Institute of Cardiovascular Disease, USA and, University of California at San Francisco, Departments of Pathology & Neurology, 1650 Owens Street, San Francisco, CA 94158, USA Tel.: ; Fax: ; yhuang@gladstone.ucsf.edu Keywords: amyloid β peptide, Alzheimer s disease, apolipoprotein E, cholesterol, lipid metabolism, neurodegenerative disorders, Parkinson s disease, statin Lipids are an essential component of cellular bilayer membranes and the major energy reserve in cells and tissues; lipid homeostasis is crucial for normal cell morphology, integrity and function. Apart from adipose tissue, lipids are most abundant in the brain, which contains approximately 60% lipids. Lipids are critical for neuronal development, plasticity, and function. Abnormal lipid metabolism contributes to the pathogenesis of several neurodegenerative disorders, including Alzheimer s disease and Parkinson s disease. Some positive clinical outcomes of statins, a class of cholesterol-lowering drugs, in Alzheimer s disease also emphasize lipids as potential therapeutic targets. Currently, it is unclear whether altered lipid homeostasis in neurodegenerative disorders reflects earlier pathological events, or in fact triggers those events. In either case, further understanding of the mechanisms involved will be of great value in developing drugs to either treat or prevent various neurodegenerative disorders. Alzheimer s disease (AD), the leading cause of dementia, affects up to 15 million people worldwide. More than 4 million Americans have been diagnosed with AD, a number which is expected to double during the next 25 years [1]. AD causes progressive, irreversible loss of cognitive function and is characterized by two neuropathological hallmarks extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) [2]. Unfortunately, despite considerable investment in neuroscience over the past three decades, only five drugs have been approved by the US FDA for AD treatment. In approximately one-third of patients, these drugs temporarily improve cognition, global functioning and the ability to conduct the activities of daily living. However, they do not appear to influence the underlying progression of the disease and do not work at all in advanced cases [3]. Novel drugs based on newly identified targets are sorely needed. AD is a complex neurodegenerative disorder that is probably caused by interactions among multiple genetic and environmental factors. Mutations in three genes, amyloid precursor protein (APP), presenilin (PS)-1 and PS-2, have been linked to early-onset (<60 years old) familial AD [4 6], which accounts for less than 5% of AD cases. The mutations all affect APP processing, leading to altered production of amyloid-β (Aβ) peptides [4,5]. Apolipoprotein (Apo)E4 has been linked genetically to late-onset (>60 years old) familial and sporadic AD, which accounts for more than 95% of AD cases, and it has a gene-dose effect on the risk and age of disease onset [7 9]. Lipid metabolism & Alzheimer s disease Lipid metabolism has long been linked to heart disease [10 13]. Recent evidence suggests a link between lipid metabolism (especially cholesterol) and susceptibility to AD [10,12 22]. In many studies, elevated plasma cholesterol levels were associated with increased risk of AD [23 26], although the interpretation of the data is still controversial [27 29]. In some studies, administration of statins, a class of cholesterol-lowering drugs, was associated with a decreased risk for AD [30 33]. Moreover, cholesterol accumulates in amyloid plaques and nerve terminals in AD brains and in aged APP transgenic mice [34]. A diet enriched with the omega-3 fatty acid docosahexaenoic acid protected against dendritic pathology and reduced amyloid burden in APP transgenic mice [35,36]. Finally, genetic studies have linked AD susceptibility to genes related to cholesterol metabolism [37 43], including ApoE, a major cholesterol transporter in the circulation and in the brain [40 44]. Therefore, abnormal lipid metabolism could be an important early event in the pathogenesis of AD (Figure 1). At the cellular level, an increase in cellular cholesterol content stimulates the production and accumulation of Aβ, a molecule of central importance in the current model of AD pathogenesis, in both cultured neurons and AD brains [45 47]. Alternatively, APP processing and Aβ production may also affect cellular lipid metabolism, leading to alterations in the generation or turnover of cholesterol or sphingolipids [48,49]. It is possible that abnormal cholesterol metabolism, which could be a consequence of the presence of ApoE4, / Future Medicine Ltd ISSN Future Lipidol. (2006) 1(4),

3 REVIEW Xu & Huang is an early event in AD pathogenesis, leading to altered APP processing and increased Aβ production and neurotoxicity, which could in turn exacerbate the lipid disorder. A deleterious feedback loop between abnormal cholesterol metabolism and Aβ production and neurotoxicity could be one of the molecular mechanisms underlying the link between lipids and AD (Figure 1). Plasma lipid metabolism & Alzheimer s disease Many studies of the relationship between plasma lipid and lipoprotein levels and the risk of AD have shown a positive correlation [17,23,24,50]. In 1998, Notkola and colleagues found that a high total cholesterol level increased the risk of developing AD [17]. Kuo and colleagues reported a similar tendency in AD patients and further showed that the plasma levels of total and lowdensity lipoprotein cholesterol (LDL-C) correlated with the amount of Aβ in AD brains [23]. This finding was confirmed in another study [51], which also showed that the association of plasma cholesterol levels with AD risk was progressively stronger with increasing pathological certainty of AD diagnosis [51]. The cholesterol AD association was also observed in a population-based study in African Americans [50]. Interestingly, elevated cholesterol levels have also been linked Figure 1. Schematic model of the relationship of lipid metabolism and neurodegenerative disorders. Statins Plasma Dietary lipids Brain Lipid disorders Altered APP processing and A production and/or accumulation Neurodegeneration and cognitive decline Aβ: Amyloid β; APP: Amyloid precursor protein. Apolipoprotein E4 to vascular dementia, suggesting a general role for abnormal lipid metabolism in neurodegeneration [24]. However, unlike total or LDL-C, elevated plasma levels of high density lipoprotein cholesterol (HDL-C) are associated with a significantly decreased risk of dementia [52]. However, other studies found no association between plasma cholesterol levels and AD risk [27,28,52], and some even suggested that lower cholesterol levels increase the risk of AD in older subjects, independently of ApoE genotype [29,53]. In addition, lower levels of cholesterol in cerebrospinal fluid have been reported for AD patients [54]. These conflicting results could reflect differences in study design, diagnostic criteria for AD, disease status or the involvement of other risk factors. They could also reflect age differences in the study subjects. Although high plasma cholesterol levels are a risk factor for early amyloidogenesis and AD in midlife, cholesterol levels are not associated with AD onset in old age [27,28]. For example, in a study of 1449 subjects aged years who were followed for an average of 21 years, elevated plasma cholesterol levels in midlife were a significant risk factor for mild cognitive impairment, which has been considered to be a predictor of AD [55]. In the same study, elevated systolic blood pressure or high plasma cholesterol levels in midlife significantly increased the risk of AD in later life [25]. In a study of the relationship between AD pathology and hypercholesterolemia, hypercholesterolemia correlated with amyloid deposition in only the youngest subjects (40 55 years of age) [26]. These findings suggest a role for midlife vascular risk factors, such as hypercholesterolemia and hypertension, in the development of AD in late life. Thus, it might not be surprising that the association between cholesterol levels and AD is weak in elderly people. It is not clear how plasma cholesterol levels affect AD risk. It is generally accepted that brain cholesterol is synthesized in situ and, owing to the blood brain barrier, plasma cholesterol has little effect on brain cholesterol levels [15,56,57]. One possibility is that elevated plasma cholesterol levels cause cerebrovascular disease, such as atherosclerosis, leading to decreased brain metabolism, neuronal dysfunction and, finally, dementia. Alternatively, both increased plasma cholesterol levels and AD could be due to other pathogenic factors, such as aging and ApoE4. In fact, plasma cholesterol levels increase with aging and in the presence of ApoE4 [10 13]. 442 Future Lipidol. (2006) 1(4)

4 Lipid metabolism in Alzheimer s and Parkinson s disease REVIEW Dietary lipids & Alzheimer s disease Some cohort studies have suggested a link between dietary lipids and AD or dementia [58,59]. Consumption of fish oil, a good source of omega-3-polyunsaturated fatty acids, is associated with reduced prevalence and incidence of AD [58 61], although not all studies support this notion [62]. However, n-6-polyunsaturated fatty acid appears to be associated with impaired cognition [63]. In aged individuals, those with dementia have lower plasma levels of docosahexaenoic acid, which is important for brain development [64]. Furthermore, in APP transgenic mice, a diet enriched in omega- 3 fatty acid (docosahexaenoic acid) protected APP transgenic mice against dendritic pathology and reduced the amyloid burden [35,36]. Thus, the prevalence and incidence of AD seems to be affected by dietary lipid composition and a healthy diet might help prevent the development and progression of AD (Figure 1). Statins & Alzheimer s disease Further support for the link between abnormal cholesterol metabolism and AD pathogenesis comes from studies demonstrating that statins are associated with a significant decrease in the prevalence of AD or dementia (Figure 1) [30 33]. These cholesterol-lowering agents (e.g., lovastatin, pravastatin, simvastatin and atorvastatin) competitively inhibit hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme regulating the cellular synthesis of cholesterol, and significantly reduce the risk and progression of cardiovascular and cerebrovascular disease [65]. In 2000, information from 368 physician practices suggested that individuals 50 years and older who were prescribed statins had a substantially lower risk of developing dementia, regardless of whether they had untreated hyperlipidemia [30]. The same effect was observed in another study [32]. Since statin use might relate to other factors indicating a healthy lifestyle, data from 2305 subjects were evaluated further, including health information, drug use and cognitive status [31]. After adjustment for gender, educational level and self-rated health, statin use was still associated with reduced risk of AD in subjects younger than 80 years of age; no significant effect was found in subjects 80 years of age and older. The potential link between statin use and cognitive function has also been assessed in older women, a group with a high risk of developing AD. In one study, statin users tended to have less cognitive impairment than nonusers [33]. Other studies indicate that atorvastatin treatment may be of some clinical benefit and could be established as an effective therapy for mild to moderate AD [66,67]. However, large prospective cohort studies did not reveal a significant decrease in the incidence of AD or dementia in statin users [68,69]. Therefore, studies are required to evaluate the role of statins in AD pathogenesis and to determine whether statins directly alter brain sterol metabolism or act through their effects on plasma cholesterol metabolism. Cholesterol metabolism & amyloid-β production Aβ is the major constituent of senile plaques in the brain and its overproduction is linked to early-onset AD [70]. In vitro, increasing levels of cellular cholesterol cause overproduction and accumulation of Aβ [45]. In vivo, hypercholesterolemia induced by a high-fat diet increases Aβ load, with an increase in plaque number and size, in APP transgenic mice [71]. In contrast, reducing cholesterol in cultured cells decreases Aβ production [45,46]. For example, simvastatin and lovastatin reduced intracellular cholesterol levels in primary neuronal cultures, resulting in decreased levels of Aβ in the medium [45]. Furthermore, guinea pigs treated with statins had a strong and reversible reduction of Aβ levels in cerebrospinal fluid and brain homogenates [45]. Statins had similar effects in human APP transgenic mice [18] and also lowered plasma Aβ levels in humans [47]. Interestingly, altering cellular cholesterol metabolism through other pathways also affects Aβ production [72 74]. For example, inhibiting the activity of acyl-coenzyme:cholesterol acyltransferase (ACAT), an enzyme which converts cholesterol to cholesterol esters, decreases Aβ production in cell cultures, suggesting that cellular cholesterol ester, but not free cholesterol, stimulates Aβ production [72]. In addition, activation of liver X receptors (LXRs), which play a key role in regulating the expression of genes involved in cellular cholesterol efflux and membrane composition [75], also decreases Aβ production [73,74]. Furthermore, LXR-α and LXR-β double knockout mice developed severe CNS neurodegeneration [76]. APP, a type I transmembrane protein, is processed proteolytically through two pathways, the amyloidogenic pathway, which generates Aβ, and the nonamyloidogenic pathway, which eliminates Aβ production (Figure 2). In the amyloidogenic pathway, APP is cleaved first by β-secretase and then by γ-secretase, generating toxic Aβ

5 REVIEW Xu & Huang Thus, increasing β- or γ-secretase activity leads to elevated levels of Aβ in the brain. However in the nonamyloidogenic pathway, APP is cleaved by α-secretase within the Aβ sequence, and the Aβ peptide is not produced. Competition between these pathways would affect the Aβ production rate and thus might affect AD progression. The effects of cellular cholesterol on these pathways have been studied by monitoring secretase activities. Increasing cellular cholesterol stimulated the amyloidogenic pathway by enhancing β-secretase and/or γ-secretase activity or by decreasing α-secretase activity (Figure 2) [77 79]. However, not all studies support this notion [80]. How does cellular cholesterol affect these two pathways? Cholesterol in the bilayer plasma membrane is not distributed evenly. Instead, cholesterol and other lipids, such as sphingolipids, are concentrated in small patches on the membrane, termed lipid rafts (Figure 2) [81]. The lipid environment within these rafts affects the function of many transmembrane receptors and enzymes [81,82]. APP and secretases are membrane-bound proteins, and cellular cholesterol content might affect their distribution or activity in the lipid rafts (Figure 2) [77,83 85]. Support for this hypothesis comes from the observation that Figure 2. Working model of the effects of membrane lipid composition on amyloid precursor protein processing and amyloid-β production. sapp α α-secretase Cholesterol-poor region Increase in cholesterol Decrease in cholesterol γ-secretase sapp β β-secretase Cholesterol- and sphingolipid-rich region (lipid raft) APP within the cholesterol-poor regions of the membrane favors the nonamyloidogenic processing by α-scretase, which diminishes amyloid-β (Aβ; green cylinder) production. However, APP within the cholesterol- and sphingolipid-rich regions (lipid rafts) of the membrane favors the sequential amyloidogenic processing by β- and γ-secretases, which generates Aβ. Thus, changes in membrane lipid composition affect the balance between these two pathways, leading to altered APP processing and Aβ production. APP: Amyloid precursor protein. APP, β-secretase and PS1 (a component of the γ-secretase complex) all reside in the detergentresistant membrane fraction, suggesting that amyloidogenic processing of APP might occur in lipid rafts [83 85]. Subsequently, the amyloidogenic processing of APP to Aβ was found to occur predominantly in the lipid rafts and β-secretase was the rate-limiting factor [77]. β-secretase activity was sensitive to changes in cellular lipid content and decreased dramatically when the lipid rafts were disrupted by the depletion of membrane cholesterol [77]. Furthermore, γ-secretase activity, which is cholesterol dependent, was localized to buoyant membrane microdomains, where C-terminal fragments of APP reside [78,86]. Unlike β- and γ-secretases, α-secretase activity increases as cholesterol levels decrease (Figure 2) [79], although its intracellular location remains controversial. Effect of amyloid-β on lipid metabolism It has been suggested that APP processing affects cellular lipid metabolism [48,49]. In cultured neurons and in transgenic mice, Aβ with 42 amino acids (Aβ 42 ) can activate neutral sphingomyelinases and downregulate sphingomyelin levels, whereas Aβ 40 reduces de novo cholesterol synthesis by inhibiting the activity of HMG-CoA reductase [49]. Therefore, maintaining lipid homeostasis could be a biological function of APP processing [49], and the pathological accumulation of Aβ could lead to abnormal lipid metabolism. Furthermore, both studies in vitro and in AD patients suggest that Aβ causes oxidative stress, leading to lipid oxidation that might contribute directly to neurodegeneration [48]. Studies also suggest that Aβ induces ozonolysis of cholesterol, leading to the formation of peroxi-derivatives that accelerate aggregation of Aβ monomers [87] and that Aβ oxidizes cholesterol at positions of 7-β and 3-β, thus leading to H 2 O 2 production [88 90]. Therefore, a deleterious feedback loop between Aβ accumulation and altered lipid metabolism could be one of the molecular mechanisms underlying the link between lipid disorders and AD. Cholesterol metabolism-related genes & Alzheimer s disease ApoE4 & Alzheimer s disease To date, more than 50 genes have been suggested to influence the risk of late-onset AD, although only a few have been accepted widely [91]. Several of these susceptibility genes are important in lipid metabolism or transport. 444 Future Lipidol. (2006) 1(4)

6 Lipid metabolism in Alzheimer s and Parkinson s disease REVIEW Among them is ApoE4, a strong genetic risk factor for late-onset sporadic and familial AD [40,42 44]. Individuals with two copies of the ApoE4 allele (2% of the total population) have a 50 90% chance of developing AD by the age of 85, and those with one copy of ApoE4 (15% of the total population) have an approximate 45% chance. In the general population, however, the chance is only approximately 20% [7]. Many hypotheses have been proposed, including the modulation of the deposition and clearance of Aβ and the formation of plaques [92 102], impairment of the antioxidative defense system [ ], dysregulation of neuronal signaling pathways [106], disruption of cytoskeletal structure and function [ ], and increased phosphorylation of tau and the formation of NFTs [110,111]. However, it remains unclear how ApoE4 contributes to AD pathogenesis. ApoE has important and diverse roles in neurobiology [10,41,42]. The brain is second only to the liver in the abundance of ApoE mrna [112]. Brain ApoE is synthesized and secreted primarily by astrocytes [113,114], but some neurons do so as well [ ]. In some neurons, brain injury induces ApoE expression [124,125]. ApoE-containing lipoproteins are found in cerebrospinal fluid (CSF), where they account for the majority of lipoproteins [126]. Furthermore, ApoE levels increase fold in response to peripheral nerve injury in a rat model [ ]. Injury-induced accumulation of ApoE also occurs in the CNS, although to a lesser extent [131]. ApoE is the major lipid transporter in the brain [40,43,132], and can bind with cholesterol and phospholipids to form lipoprotein particles. As a ligand for cell-surface lipoprotein receptors, such as the LDL receptor and the LDL receptorrelated protein [132], ApoE aids in the regulationof lipid transport and clearance in the CNS [10,132]. These processes are essential for neuronal remodeling and the formation of dendrites and synapses [133]. ApoE appears to take up lipids generated after neuronal degeneration and redistributes them to cells requiring lipids for proliferation, membrane repair or remyelination of new axons [131,134]. ApoE has isoformspecific effects on neurite remodeling, with ApoE3 stimulating neurite outgrowth and ApoE4 inhibiting it [107,135,136]. ApoE may also protect against motor and cognitive defects due to acute head injury [137] or stroke [138]. Increased production of ApoE3, but not ApoE4, in the hippocampus stimulates repair of local lesion-induced damage [139]. Moreover, synaptic and dendritic alterations and significant learning deficits, all of which have been associated with local neurite remodeling, are observed in ApoEdeficient mice [140] and ApoE4 transgenic mice [ ]. In transgenic mice expressing human ApoE on a mouse ApoE-null background, ApoE4 mice, but not ApoE3 mice, perform poorly in a watermaze test [ ], indicating a striking memory deficiency associated with ApoE4. Notably, ApoE3, but not ApoE4, protects against excitotoxin-induced neuronal damage in mice [141]. Finally, ApoE3 stimulates, but ApoE4 inhibits, neuronal sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing ApoE3 or ApoE4 [147]. ApoE4 is associated with elevated plasma and LDL-C levels, which also increase AD risk. Thus, ApoE4 and abnormal cholesterol levels could be independent risk factors for AD, or the association with AD could be mediated by effects of ApoE4 on cholesterol metabolism. A recent study suggested that vascular and lipid factors do not mediate the association between ApoE4 and AD [148]. Other cholesterol metabolism related genes & Alzheimer s disease AD appears to be linked to cholesterol metabolism-related genes other than ApoE [56,91]. For example, two studies identified an association between AD and two single nucleotide polymorphisms in Cyp46, an enzyme that converts cholesterol to 24 S-hydroxycholesterol for excretion through the blood brain barrier [37,38]. One of the polymorphisms was also associated with increased Aβ levels in CSF [37]. However, two other studies failed to show such an association [149,150]; one suggested that an intronic marker of CYP46 interacts with age and ApoE genotype [150]. AD has also been linked to a polymorphism in ATP-binding cassette, subfamily A, member 1 (ABCA1), a cellular cholesterol transporter [39]; however, that association was not found in a subsequent study [151]. In mice, ABCA1 is required for maintaining normal CNS ApoE levels and for lipidation of astrocyte-secreted ApoE [152,153], and deficiency of ABCA1 increases Aβ deposition in human APP transgenic mice [ ]. Therefore, although links between AD and cholesterol metabolismrelated genes, other than ApoE4 seem to support the importance of abnormal cholesterol metabolism in AD pathogenesis, the association between 445

7 REVIEW Xu & Huang those genes and AD, except for the case of ApoE4, remains weak. The significance of those genes in the pathogenesis of AD merits further investigation both in vitro and in vivo. Lipid metabolism & Parkinson s disease Parkinson s disease (PD) is a chronic, progressive neurodegenerative movement disorder caused by the degeneration of dopamine-producing nerve cells in the brain [157]. Familial PD has been linked to mutations in the α-synuclein gene [157,158]. Since α-synuclein is the primary component of Lewy bodies, it is thought to have a central role in the pathogenesis of PD. However, the mechanisms of its toxicity and aggregate formation remain unclear [159]. Several studies using different approaches have concluded that lipids are an important modifier of α-synuclein toxicity [ ]. Synaptosomal fractions of brain lystates are enriched in α-synuclein [163]. Interestingly, the amino terminus of α-synuclein resembles the lipid-binding domains of some apolipoproteins, suggesting a potential interaction of α-synuclein with lipids [160]. In vitro, α-synuclein does interact with small unilamellar vesicles containing sphingomyelin and cholesterol, affecting lipid packing in the vesicles [164]. Furthermore, the formation of α-synuclein multimers correlated well with the length and degree of saturation of fatty acids added to cells [161]. This finding suggests that lipids can modulate α-synuclein oligomerization, a key nucleation step in the formation of prefibrillar and fibrillar aggregates of α-synuclein. Thus, manipulation of the fatty acid composition in brains could be a way to reduce the formation of toxic α-synuclein species [162]. In fact, dietary lipids can affect PD progression. For example, dietary unsaturated fatty acids might have a protective role in PD [165], although a previous study does not support this notion [166]. A genome-wide screening in yeast also supports the notion that lipid metabolism modulates α-synuclein toxicity [167]. In yeast, expression of α-synuclein alone caused only modest reduction in viability. In the screening, 86 of 4850 mutant yeast colonies were highly sensitive to α-synuclein toxicity. Remarkably, of 57 toxicity-modifier genes with known biological functions, 18 (32%) were related to lipid metabolism and vesicle-mediated transport. In contrast, when a mutant huntingtin fragment was used to identify modifier genes for Huntington s disease, only a few genes fell into these categories [167]. Lipid metabolism & other neurodegenerative disorders The role of lipid metabolism in other neurodegenerative disorders has not been well established. However, increasing evidence suggests that altered lipid metabolism could be a general mechanism in neurodegeneration. Many neurodegenerative disorders are accompanied by highly insoluble protein aggregates within characteristic neuronal populations. Lipids can affect the formation of some of those abnormal structures in vitro [161,168,169]. For example, in amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder that mainly affects motor neurons in the brainstem and spinal cord, superoxide dismutase (SOD)1- immunoreactive inclusions are found in spinal cord neurons; similar inclusions are found in SOD1 mutant mice [170]. Interestingly, longchain unsaturated fatty acids promoted aggregate formation of mutant SOD1 in a dose- and timedependent manner, suggesting that unsaturated fatty acids might cause mutant SOD1 to adopt an aggregation-prone conformation [168]. Prion disease, an infectious neurodegenerative disorder, is characterized by a pathological conformation of prion (Pr) protein (P) [171]. Normal PrP and the pathological scrapie PrP were associated with lipid rafts [ ]. It has been suggested that cholesterol is essential for the cell-surface localization of cellular PrP, which is necessary for prion conversion [169]. Oxidative stress is observed in many neurodegenerative disorders [174]. It usually leads to lipid oxidation and altered lipid metabolism. Abnormalities in sphingolipid and cholesterol metabolism have been detected in the spinal cord in ALS patients and in Cu/Zn-SOD mutant mice [175]. In ALS mice, inhibition of sphingolipid synthesis appears to prevent the accumulation of ceramides, sphingomyelin and cholesterol esters and protects motor neurons from death induced by oxidative insults [175]. Conclusion & future perspective The pathogenesis of neurodegenerative disorders usually involves the interaction of multiple genetic and environmental risk factors. Although the underlying molecular mechanisms in many of these disorders are still poorly understood, increasing evidence suggests that abnormal lipid metabolism is a piece of the puzzle. Long before clinical symptoms are apparent, altered lipid metabolism might help establish an early pathological foundation for the development of 446 Future Lipidol. (2006) 1(4)

8 Lipid metabolism in Alzheimer s and Parkinson s disease REVIEW neurodegenerative diseases. Alternatively, disturbed lipid metabolism could be a consequence of other factors related to neurodegeneration, including ApoE4, Aβ accumulation, oxidative stress and inflammatory reactions. Regardless of which one goes first, abnormal lipid metabolism and neuronal deficits could form a deleterious feedback loop that promotes disease progression. Thus, a better understanding of the involvement and mechanisms of altered lipid metabolism in various neurodegenerative disorders is essential in terms of both mechanistic study and therapeutic intervention. Manipulation of lipid metabolism disorders through dietary and/or medical treatment could be beneficial for treating, or even preventing, neurodegenerative disorders. Clearly, further study is required to address many unsolved questions. For example, is abnormal lipid metabolism a cause or a consequence of neurodegenerative disorders? How does plasma cholesterol level affect APP processing and Aβ production in brains? Are statins really beneficial for AD patients? If so, what are the underlying molecular and cellular mechanisms? Does ApoE s role in AD pathogenesis depend on the alteration of brain or neuronal lipid metabolism? How can lipids modulate the conformation, aggregation and toxicity of α-synuclein in neurons? Can the manipulation of lipid metabolism in the brain through dietary or medical treatment be beneficial for treating or even preventing neurodegenerative disorders? To answer these questions, new cell models and transgenic and gene-targeted mouse models need to be developed, with further prospective clinical trials undertaken. Acknowledgements This work was supported in part by National Institutes of Health grants P01 AG We thank Robert W Mahley and Karl H Weisgraber for critical reading of the manuscript, Karina Fantillo for manuscript preparation, Stephen Ordway and Gary Howard for editorial assistance, and John CW Carroll for graphics. Executive summary Alzheimer s disease Alzheimer s disease (AD) is the leading cause of dementia worldwide. AD is a multifactorial disease characterized clinically by progressive irreversible loss of cognitive functions and pathologically by the loss of synapses and neurons and the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Mutations in three genes, amyloid precursor protein (APP), presenilin (PS)1 and PS2, have been linked to early-onset familial AD. Apolipoprotein E4 has been linked to late-onset familial and sporadic AD. Plasma lipid metabolism & Alzheimer s disease A positive correlation between plasma total and low-density lipoprotein-cholesterol levels and AD risk has been identified in many, but not all, studies. Plasma cholesterol does not significantly affect brain cholesterol levels, owing to the presence of the blood brain barrier. Thus, it is unclear how plasma cholesterol affects AD risk. One possibility is that elevated plasma cholesterol levels cause cerebrovascular disease (e.g., atherosclerosis), leading to decreased brain metabolism, neuronal dysfunction and finally dementia. Cholesterol-lowering drugs, statins & Alzheimer s disease Statin use is associated with a significant decrease in the prevalence of AD or dementia in many retrospective cohort studies. Several prospective cohort studies did not reveal a significant decrease in the incidence of AD or dementia in statin users. It is not clear whether, or how, statins affect AD risk. Studies suggest potential effects that are dependent on, or independent of, cholesterol-lowering. Cholesterol metabolism & amyloid-β production Both in vitro and in vivo studies demonstrate that increasing cellular cholesterol stimulates amyloid-β (Aβ) production and vice versa. Cellular cholesterol affects Aβ production by modulating activities of different secretases in lipid rafts. Increasing cellular cholesterol stimulated the amyloidogenic pathway by enhancing β-secretase and/or γ-secretase activity or by decreasing α-secretase activity, although not all studies support this notion. Effect of Aβ on lipid metabolism Altered APP processing and Aβ production might affect the cellular metabolism of sphingolipids and cholesterol, leading to altered lipid homeostasis. Both in vitro and in vivo studies suggest that Aβ can cause oxidative stress, leading to lipid oxidation that might contribute directly to neurodegeneration

9 REVIEW Xu & Huang Executive summary ApoE4 & AD ApoE4 is a major risk factor for AD and has a gene-dose effect on disease risk and age-of-onset. It remains unclear how ApoE4 contributes to AD pathogenesis, although many hypotheses have been proposed. ApoE4 has both Aβ-dependent and Aβ-independent effects on lipid metabolism and in AD pathogenesis. Lipid metabolism & Parkinson s disease Parkinson s disease (PD) is a chronic, progressive neurodegenerative movement disorder characterized by degeneration of dopamine-producing nerve cells and formation of Lewy bodies in neurons. α-synuclein is the primary component of Lewy bodies and is considered to have a central role in PD pathogenesis. Cellular lipids can modulate the conformation, aggregation and toxicity of α-synuclein. Conclusions The pathogenesis of neurodegenerative disorders usually involves the interaction of multiple genetic and environmental factors. Although the underlying molecular mechanisms for many neurodegenerative disorders are still poorly understood, abnormal lipid metabolism appears to be a piece of the puzzle. Regardless of whether it is a cause or consequence, in many neurodegenerative disorders, a potential deleterious feedback loop between abnormal lipid metabolism and neuronal deficits could promote disease progression. Manipulation of lipid metabolism disorders through dietary and/or medical treatment could be beneficial for treating, or even preventing, neurodegenerative disorders. Bibliography Papers of special note have been highlighted as either of interest ( ) or of considerable interest ( ) to readers. 1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA: Alzheimer disease in the US population. Prevalence estimates using the 2000 census. Arch. Neurol. 60, (2003). 2. Selkoe DJ: The molecular pathology of Alzheimer s disease. Neuron 6, (1991). 3. 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