review article the impact of cholesterol, dha, and ...family mainly involved in the cholesterol...
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Hindawi Publishing CorporationBioMed Research InternationalVolume 2013, Article ID 814390, 16 pageshttp://dx.doi.org/10.1155/2013/814390
Review ArticleThe Impact of Cholesterol, DHA, and Sphingolipids onAlzheimerās Disease
Marcus O. W. Grimm,1,2,3 Valerie C. Zimmer,1 Johannes Lehmann,1
Heike S. Grimm,1 and Tobias Hartmann1,2,3
1 Experimental Neurology, Saarland University, Kirrberger Street 1, 66421 Homburgr, Saar, Germany2Neurodegeneration and Neurobiology, Saarland University, Kirrberger Street 1, 66421 Homburg, Germany3Deutsches Institut fuĢr DemenzPraĢvention (DIDP), Saarland University, Kirrberger Street 1, 66421 Homburgr, Saar, Germany
Correspondence should be addressed to Marcus O. W. Grimm; [email protected] andTobias Hartmann; [email protected]
Received 30 April 2013; Accepted 13 July 2013
Academic Editor: Cheng-Xin Gong
Copyright Ā© 2013 Marcus O. W. Grimm et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Alzheimerās disease (AD) is a devastating neurodegenerative disorder currently affecting over 35 million people worldwide.Pathological hallmarks of AD are massive amyloidosis, extracellular senile plaques, and intracellular neurofibrillary tanglesaccompanied by an excessive loss of synapses. Major constituents of senile plaques are 40ā42 amino acid long peptides termedš½-amyloid (Aš½). Aš½ is produced by sequential proteolytic processing of the amyloid precursor protein (APP). APP processing andAš½ production have been one of the central scopes in AD research in the past. In the last years, lipids and lipid-related issues aremore frequently discussed to contribute to the AD pathogenesis.This review summarizes lipid alterations found in AD postmortembrains, AD transgenic mouse models, and the current understanding of how lipids influence the molecular mechanisms leading toAD and Aš½ generation, focusing especially on cholesterol, docosahexaenoic acid (DHA), and sphingolipids/glycosphingolipids.
1. APP Processing
Amyloid plaques are composed of aggregated amyloid-š½ pep-tides, derived from sequential proteolytic processing of theamyloid-precursor protein (APP), a type-I transmembraneprotein with a large extracellular N-terminal domain anda short intracellular C-terminal tail [1]. APP and its genefamily members, the APP-like proteins APLP1 and APLP2,are highly conserved proteins expressed in numerous speciesand tissues pointing out their physiological importance[2]. Indeed, triple knockout of APP/APLP1/APLP2 in miceresults in postnatal lethality involving brain developmentabnormalities and cortical dysplasia [3]. In contrast, sin-gle knockout of APP has a minor phenotype consistingof reduced body weight [2], commissure defects [4], andhypersensitivity to epileptic seizures [5] demonstrating themutual functional compensation of the gene family membersand additionally illustrates the physiological role of APP.Furthermore, a potential contribution to the formation of
dendritic and synaptic structures as well as in long-term po-tentiation (LTP) [6ā8] suggests a possible impact on cognitivefunction.
APP can be cleaved in two distinct pathways, the amyl-oidogenic andnonamyloidogenic pathways.Thenon-amyloi-dogenic processing of APP by š¼-secretases avoids the forma-tion of Aš½ peptides by cleaving inside the Aš½ domain [9].Thereby, the large N-terminal ectodomain š¼-secreted APP(sAPPš¼) is released into the extracellular matrix, whereas theshort C-terminal part (š¼-CTF) remainswithin themembranefor further processing. Notably, sAPPš¼ has neuroprotectiveand memory enhancing properties [10, 11], hypothesizingthat sAPPš¼ might mediate a major physiological functionof APP [12]. The š¼-secretases belonging to the ADAMfamily (a disintegrin and metalloprotease), in particularADAM10 and ADAM17 (tumor necrosis factor š¼ convertingenzyme/TACE), have emerged as predominant š¼-secretases[13ā15]. Like APP itself, these proteins are type I integralmembrane proteins.
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The amyloidogenic pathway, on the other hand, is ini-tiated by the š½-secretase BACE1 (beta-site APP cleavingenzyme) that generates soluble š½-secreted APP (sAPPš½)and the membrane-tethered fragment š½-CTF. BACE1 is amembrane-bound aspartyl protease belonging to the pepsinfamily, expressed in neurons [16]. The main š½-secretaseactivity is found in the secretory pathway including the Golgicompartments, secretory vesicles, and endosomes [17, 18].Apart from its amyloidogenic effect, less is known about thephysiological function of BACE1; however, in BACE1 knock-out mice, myelination is affected [19, 20]. Initial cleavageof APP by š¼-secretase in the non-amyloidogenic pathway,or by š½-secretase in the amyloidogenic pathway, is typicallyfollowed by š¾-secretase processing, a multimeric complexconsisting of at least four subunitsāpresenilin 1 (PS1) orpresenilin 2 (PS2), anterior pharynx defective 1 homologue(APH1), presenilin enhancer 2 (PEN2), and nicastrin [21]with PS1/PS2 being the catalytic centre [22, 23]. Importantly,mutations inside the PS genes are responsible for early onsetAD [24]. PS1 and PS2 are multitransmembrane spanningaspartyl proteases cleaving the C-terminal stubs š¼- andš½-CTF within the centre of their transmembrane domain[25], generating p3 and Aš½ peptides of varying length (e.g.,Aš½38, Aš½40, and Aš½42). Among the Aš½ species generated,hydrophobic Aš½42 peptides self-aggregate to small oligomersbefore being manifested as senile plaques composed of adense core of amyloid fibrils [26, 27]. Simultaneously, theAPP intracellular domain (AICD), which is discussed toregulate gene transcription, is released into the cytosol [28].The substrate APP and the secretases involved in APPcleavage are all transmembrane proteins, suggesting that thesurrounding lipid microenvironment may play a pivotal rolein the pathogenesis of the disease.
2. Cholesterol and AD
The human brain has a very high cholesterol content, mainlyassociated with myelin. Due to the limited transport overthe blood-brain barrier (BBB), the brain cholesterol levelis largely independent of the serum cholesterol concentra-tions. The vast majority of brain cholesterol is providedby glial de novo synthesis. Noteworthy, cholesterol trans-port between neurons and glia cells is mostly providedby clusterin/apolipoprotein J (ApoJ) and apolipoprotein E(ApoE) containing lipoproteins. Intriguingly, the ApoEš4allele genotype is the predominant genetic risk factor forAD, whereas the š2 allele seems to be protective and š3being the most common form. A possible explanation forthis might be reduced Aš½-clearance and/or increased for-mation of amyloid in the presence of the š4 genotype,but many other mechanisms have also been suggested [29ā31]. Recent genome-wide association studies (GWASs) havegreatly extended our knowledge on AD risk genes. Interest-ingly, two main functional risk clusters were identified. MostGWAS-identified risk genes are either linked to inflammationor to lipid/membrane processes. Besides ApoE polymor-phism, single-nucleotide polymorphisms for clusterin (CLU),ABCA7, and PICALMwere discovered to raise the individualrisk for developingAD [32ā34].On one hand, clusterin serves
as a major lipid binding protein [35]. Interestingly, clustrinmRNA and protein levels are increased in AD, thereby, cor-relating with disease severity [36, 37]. Furthermore, clusterinmay be involved in modulation of apoptosis, inflammation,and Aš½ aggregation [38ā40]. ABCA7, belonging to the ATP-binding cassette transporters, is expressed throughout thebrain and especially in hippocampal neurons [41, 42]. ABCA7is involved in cholesterol efflux from cells to ApoE and affectsAPP processing [43]. These genetic links between AD riskand cholesterol are supported by strong epidemiological evi-dence linking hypercholesterolemia with dementia [44, 45].Likemany other life-style influencedAD risk factors, elevatedblood cholesterol levels, even if only moderately increased,are most relevant if present at midlife [46]. Additionally,elevated 24OH-cholesterol levels were observed in the serumof AD patients [47].
Cholesterol is an essential component of mammalian cellmembranes. Based on its extraordinary structure, consistingof a fused rigid ring system, a polar hydroxyl group, and ahydrocarbon tail, cholesterol is essential for bilayerās functionand organisation. Due to the impact of the rigid ring system,cholesterol can increase the order within the membraneand thereby affects membrane fluidity. Especially in lipidmicrodomains, envisioned as so-called ālipid rafts,ā primarilyfound in the plasma membrane, the trans-Golgi, and endo-somal membranes, this feature is extremely important. Lipidrafts are strongly enriched in sphingomyelin, glycosphin-golipids, and cholesterol. Cholesterol provides tight packingof the lipids in these microdomains. Some membrane pro-teins are preferentially sited in these ordered microdomains.Mechanistically important is the transient colocalization ofAPP with the amyloidogenic secretases, š½-secretase, and š¾-secretase, in the lipid rafts, pointing out that within theamyloidogenic pathway the close colocalization of theseproteins is, at least partly, mediated by cholesterol [48, 49].Nonamyloidogenic processing and theš¼-secretases, however,are localized outside the lipid rafts [50]. This characteristicimplies the possible regulation of the nonamyloidogenic andamyloidogenic pathways by altered membrane cholesterolamounts. Indeed, evidence suggests that cholesterol tends toform complexes with š½-CTF and potentially with full-lengthAPP.Thereby, the translocation ofš½-CTF/APP is promoted tothe cholesterol-enriched microdomains and thus providingthem to the amyloidogenic processing [51, 52]. Additionally,it is well established that cholesterol directly stimulatesš½- andš¾-secretases; vice versa cholesterol depletion by cyclodextrinor statins leads to a decreased activity [53ā55]. Recently, itwas described that statins influence APP maturation andphosphorylation not by cholesterol lowering but by theloss of cholesterol precursors [56]. Remarkably, cholesterolfurther affects the thickness of the lipid bilayer which directlyinfluences the š¾-secretase cleavage activity and specificity.With increasing membrane thickness, smaller Aš½ species(e.g., Aš½38 and Aš½40) were preferentially produced, whereasAš½42/43 only occurred in smaller amounts [57]. Addition-ally, š¼-secretase cleavage is increased by lowering cholesterollevels. This effect was attributed to increased membrane flu-idity and impaired APP internalisation. After treatment with
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lovastatin, ADAM10 protein level was elevated [50]. Asidefrom its impact on the Aš½ generation, cholesterol might evenmodify Aš½ aggregation and the subsequent neurotoxicity.Under physiological conditions, mainly monomeric Aš½ pep-tides develop fromAPP processing [58].Though, in AD thesemonomers are prone to form oligomers, protofibrils, andfibrils, whereby the oligomers are considered to be the mosttoxic subspecies [59]. It was highlighted that cholesterol-enriched microdomains promote amyloid aggregation, whiledepletion of cholesterol leads to reduced aggregation [60].Recent findings implicated that cholesterol facilitates š½-sheetformation by direct interaction with Phe19 amino acid of theAš½ peptide [61]. In line with these findings, some studiesshowed a relationship between elevated cholesterol level andincreased toxicity of Aš½ oligomers [62, 63]. Contradictory tothis, other investigations reported cholesterol to be protective[64, 65]. Hence, although cholesterol is essential for humanbrain development and function, it can as well be attributedto a potent role in mediating aggregation and neurotoxicity.
In line with the strong impact of cholesterol on APPprocessing, there is evidence that the cleavage products ofAPP themselves affect cholesterol metabolism. In mouseembryonic fibroblasts deficient inAPP/APLP2ā/ā or PS1/2ā/āand therefore unable to produce Aš½, cholesterol levels werehighly elevated. Interestingly, these cholesterol aberrationswere abrogated by treatment with Aš½1-40 displaying anegative feed-back cycle of Aš½1-40 by inhibiting the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), therate-limiting step in cholesterol de novo synthesis [66, 67].Additionally, decreased membrane fluidity and increasedcholesterol content in lipid rafts were observed in cellsdevoid of Aš½ [68]. Within the APP family of proteins, APPapparently has an especially important role for cholesterolhomeostasis. In APP knock-out mice, cholesterol is stronglyincreased [66, 69], and APP knockout has a number of addi-tional cholesterol- and lipid-related consequences, includingreduced diet-dependent atherosclerosis [70] and increasedNiemann-Pick cholesterol phenotype [71]. To some part, thisappears to be caused by a lack of AICD, resulting in alteredLRP1 levels [72]. LRP1 belongs to a lipoprotein-receptorfamily mainly involved in the cholesterol uptake of neu-rons, whereby cholesterol is provided by ApoE-containinglipoproteins [72]. Changes in membrane cholesterol contentwill trigger homeostatic actions affecting the regulation andmembrane content of many other lipids. Accordingly, manyother lipids affect the cholesterol regulation and several ofthese lipids are targeted by APP/Aš½ or themselves change Aš½production.
Taking all of these findings into consideration (Figure 1;See Table S1 in Supplementary Material available onlineat http://dx.doi.org/10.1155/2013/814390), pharmacologicalintervention in cholesterol metabolism might be a possibletarget in AD treatment. It seems likely that cholesterollowering by administration of HMGCR inhibitors (e.g.,statins) might refer to reduced Aš½ levels accompanied byslower cognitive decline and improved mental status.
Animal model studies associated hypercholesteremiawith elevated Aš½ levels [80ā82]. On the opposite, reduced Aš½
accumulation was achieved after administration of choles-terol lowering drugs (e.g., statins), underlining their potentialrole in the disease treatment [83ā86]. However, one studyreported unaffected Aš½ levels, whereas another one evenobserved increased Aš½ deposition [87, 88]. Interestingly, thelatter alteration was only detected in female mice. Thesedeviations might be contributed to differences in animalmodels, used drugs, and period of drug administration. Apotential beneficial effect of cholesterol lowering drugs wasfurther investigated in observational studies and randomizedcontrolled trials, whereas many observational studies withhigh number of participants associated statin intake withreduced development of AD [89ā91], others exhibited nodifferences [92, 93]. However, recent randomized, double-blind, placebo-controlled studies reported no benefit of statinuse in individuals suffering from mild to moderate AD [94,95]. Since in these trials patients were already affected byAD, statins might be ascribed to a more preventive thantherapeutic function. Thus, further studies have to evaluatea protective effect in earlier clinical stages.
3. Docosahexaenoic Acid andAlzheimerās Disease
Docosahexaenoic acid (DHA) is an essential š-3 polyun-saturated fatty acid (PUFA) mainly found in marine food,especially in oily fish. Only a small amount of DHA canbe produced endogenously by synthesis out of š¼-linoleicacid through elongation and desaturation [96], whereas themain DHA is provided by dietary intake. Approximately60% of the unsaturated fatty acids in neuronal membranesconsist of DHA, thus, representing the most common š-3 fatty acid in the human brain. DHA rapidly incorporatesinto phospholipids of cellular membranes and changes themembrane fluidity by the formation of highly disordereddomains concentrated in PUFA-containing phospholipidsbut depleted in cholesterol (reviewed in [97]). Especiallyin synapses, these alterations in membrane fluidity play animportant role in neurotransmission, ion channel formation,and synaptic plasticity. This suggests a potential role of DHAin memory, learning, and cognitive processes. In young rats,the administration of DHA leads to an improved learningability [98]. Additionally, DHA is involved in neuronal dif-ferentiation [99], neurogenesis [100], and protection againstsynaptic loss [101].Therefore,DHA is discussed to be involvedin pathological processes of AD.
DHA is decreased in certain regions of AD postmortembrains, like pons, white matter and, in particular, frontal greymatter, and hippocampus [102]. Additionally, peroxidationproducts of DHA, which is very susceptible to lipid peroxi-dation due to its six double bounds, are elevated in AD brainshypothesizing that DHA loss can be ascribed to the increasedoxidative stress [103]. These lipid alterations seem to occurnot only in advanced AD patients but also in early stages ofthe disease [104].
Several epidemiological studies tried to correlate DHAplasma levels or the amount of dietary intaken fish withcognitive decline. The Rotterdam study presented the first
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Statins
N-terminus
C-terminus
APP
Aš½
Amyloidogenicprocessing
š½-secretase š¾-secretase
Aš½
HOCholesterol
HMG-CoA reductase
Shift towards lipid rafts ā
-BACE1 protein level ā-Secretase activity ā
-PS1/PS2 gene expressionā-Secretase activity ā
Aggregation ā
Cholesterol de novo synthesis
š¼-secretase
Nonamyloidogenicprocessing
-ADAM10 gene expressionā
-sAPPš¼ level/secretase activity ā
Aš½
Toxic oligomers ā
Figure 1: Schematic representation of the proposed mechanisms of cholesterol on APP processing and Aš½ aggregation.
findings about an inverse correlation between increased fishintake and all-cause dementia [105]. However, reexaminationwith a longer follow-up period found no association betweendietary intake of š-3 fatty acids and dementia [106]. Never-theless, further studies like the PAQUID study [107] or theCHAP study [108] supported the protective effect of fish orDHA consumption initially found in the Rotterdam study.These effects were even more pronounced in individuals notcarrying the ApoE š4 allele [109, 110].
Beside the epidemiological studies, findings from animalmodels and in vitro experiments suggest that increaseddietary intake of DHA is associated with a reduced riskof AD. In a 3xTg-AD mouse model, that exhibits bothAš½ and tau pathologies [111], DHA supplementation causeda significant reduction in soluble and intraneuronal Aš½levels as well as tau phosphorylation [112]. Similar resultswere obtained with APPSwedish transgenic mice, revealingsignificant plaque reduction in the hippocampus and parietalcortex accompanied by alterations of APP cleavage products[113]. In AD-model rats, produced by infusion of Aš½1-40 intothe cerebral ventricle, DHA also improved learning ability[114]. In vitro, Aš½ fibrillation was found to be decreased inthe presence of DHA [73].
Recently, we and others elucidated the molecular mech-anisms involved in the reduced Aš½ burden in the presenceof DHA (summarized in Table 1). In the neuroblastoma cellline SH-SY5Y, DHA directly inhibited amyloidogenic š½- andš¾-secretase activities, resulting in a dose-dependent reduc-tion of Aš½ levels. On the other hand, non-amyloidogenicAPP processing was increased in DHA-treated cells, as weobserved elevated sAPPš¼ levels caused by an enhancedADAM17 protein stability [74]. Interestingly, DHA exhibited
various interactions with cholesterol homeostasis. Beside adirect inhibition of the HMGCR, DHA induced a cholesterolshift from lipid raft to the nonraft fractions, illustrating analternative secretase activity modulating pathway [74]. Inline with these findings the DHA-mediator NPD1, derivedfrom DHA processing by cytosolic phospholipase A2 and 15-lipooxygenase, is known to directly affect APP processingresulting in elevated sAPPš¼ and lower sAPPš½ and accord-ingly Aš½ levels [75, 76]. Interestingly, phospholipase A2 and15-lipooxygenase and as a consequence NPD1 were foundto be reduced in the hippocampus of AD patients and inAD mouse models [75, 76]. Beside the observed shift ofAPP processing from the amyloidogenic pathway to the non-amyloidogenic pathway, NPD1 also acts neuroprotective bydownregulating inflammatory signalling, apoptosis, and Aš½-induced neurotoxicity [76, 115].
These findings indicate a possible therapeutic use ofDHA in preventing, modulating, or improving AD progres-sion. Clinical trials, however, delivered ambiguous resultsconcerning DHA supplementation and cognitive functionssuggesting a limited benefit depending on the disease stageand ApoE allele genotype [116ā118]. Further investigationswith great cohorts have to clarify whether DHA has morepreventing than therapeutic effects by including only patientsin the earliest stages of memory decline. More recently, anadvanced DHA formulation containing several diet-derivedmolecules to enhance DHA activity resulted in a number ofclinical trials that resulted in various degrees of cognitivebenefit. The benefit was most pronounced in patients withvery mild to mild AD but less in mild to moderate ADpatients [119, 120]. Most recently, at the ADPD conference2012, Scheltens reported on an open-label extension study in
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Table 1: Summary of mechanisms of DHA and DHA derivateson APP processing. DHA both affects amyloidogenic and non-amyloidogenic pathways via multiple mechanisms resulting in adecrease in Aš½ production. In opposite to cholesterol it has beenreported that DHA decreases Aš½ aggregation and toxicity. Directeffects of DHA on APP processing are further enhanced by a DHA-mediated decrease in cholesterol de novo synthesis [73ā79].
(a) Effect of DHA
Affected pathway Mechanism of actionNonamyloidogenicprocessing
sAPPš¼ āADAM 17 protein stability ā
Amyloidogenic processing
Aš½ āš½-Secretase activity āEndosomal BACE1 āš¾-Secretase activity āPS1 shift: raft ā non-raft
Aš½ Oligomerization andtoxicity
Aš½ Fibrillation āSoluble toxic oligomers āAš½ Phagocytosis ā
Cholesterol homeostasisHMG-CoA reductase activity āCholesterol de novo synthesis āCholesterol shift: raft ā non-raft
Other non-APP-mediatedpathways/mechanisms
SorLA/R11 ā, a sorting proteinreduced in ADNeuronal differentiation āProtection against synaptic loss,Synaptogenesis āNeurogenesis āInflammation āReactive oxidative species ā
(b) Effect of DHA derivates
Affected pathway Mechanism of action
NPD1
Nonamyloidogenicprocessing
sAPPš¼ āADAM 10 maturation ā
Amyloidogenicprocessing
Aš½ āsAPPš½ āBACE 1 protein level ā
Aš½ Toxicity Neuroprotective and antiapoptoticSoluble toxic oligomers ā
very mild to mild AD patients with continuous increase inmemory performance over the study period of 48weeks [121].
4. Sphingo- and Glycosphingolipids
Sphingolipids are a heterogeneous group of lipids, struc-turally based on the 18-carbon amino alcohol sphingosinewhich is synthesized from palmitoyl-CoA and serine byserine palmitoyl-CoA transferase (SPT), representing therate-limiting step in sphingolipid synthesis and shown to beregulated by AICD [122]. Ceramide (Cer) is an importantbranching point for the synthesis of different sphingolipid
subspecies. For example, sphingomyelin (SM) is generatedout of Cer by SM-synthase, whereas the neutral sphin-gomyelinase (nSMase) catalyzes the turnover of SM to Cer.Glycosylation of Cer results in the production of glycosphin-golipids which can be further processed to gangliosides. Thecerebroside synthase adds a galactose moiety to Cer whichis the first step towards the formation of sulfatides. Finally,the decomposition of Cer is provided by the ceramidasereceiving sphingosine which itself can be phosphorylated tosphingosine-1-phosphate (S1P). First evidence of sphingolipidmetabolism being involved in neurodegenerative diseaseswas derived from investigations of lysosomal storage diseases(LSDs). This group of inherited metabolic disorders is char-acterized by accumulation of different sphingolipids due todysfunction or deficiency of the corresponding lysosomalenzymes. Importantly, affected patients clinically developprogressive cognitive decline resulting in early dementia.Additionally, AD-related pathologies like Aš½ accumulationand hyperphosphorylation of tau, leading to neurofibrillarytangles, can be observed [123, 124]. Beside these similaritiesbetween AD and LSD, several studies of AD postmortembrains indicate that the sphingolipid metabolism is alteredduring AD progression, further substantiated by biochemicalstudies, linking sphingolipids to APP processing [125ā131](Figure 2).
4.1. Ceramide. The majority of postmortem brain tissueanalysis found elevated Cer levels in the grey and whitematters of AD patients. These alterations were observedeven in early stages of AD hypothesizing that these mightpromote the development of the disease [125, 128, 131, 132].In line with these findings, gene expression abnormalities ofthe key enzymes that control sphingolipid metabolism werefound in AD patients: enzymes involved in glycosphingolipidsynthesis (e.g., UDP-glucose ceramide glucosyltransferase)were altered accompanied by changes in enzymes resultingin the accumulation of Cer (e.g., serine palmitoyltransferase,neutral sphingomyelinase, and acid sphingomyelinase) [131,133]. Recently, Mielke et al. reported in a 9-year-follow-up study that even elevated baseline serum Cer levels areassociated with a higher risk (up to 10-fold) of developing AD[134], indicating that serum Cer is associated with incidentAD.
In contrast to the results obtained from AD postmortembrains, the analysis of AD mouse models revealed incon-sistent data. Cer levels are elevated in the cerebral cortexof APPSL/PS1Ki transgenic mice, whereas the correspondingsingle-transgenic mice did not show this alteration [135].Furthermore, in APPSL/PS1M146L transgenic mice, in whichthe time course of pathology is closer to that seen inmost cur-rently available models, Cer did not accumulate in disease-associated brain regions (cortex and hippocampus) [136].These different findings might be attributed to the variousmouse models used in these studies [135, 136]. The authorssuggest that APPSL/PS1Kimice, compared to the othermousemodels, produce exceeding amounts of N-truncated Aš½x-42,also found in AD brains [135].
It is well established that ceramides induce apoptosisand exhibit neurotoxic properties [137ā139]. Interestingly,
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Nonamyloidogen
ic pathway
Amyloidogenic pathway
GM1
p3 Aš½
Aš½
š¼-CTF
š¼-cleavage
š¾-cleavage
APP
AICD
APP
mat
urat
ion
Gangliosides
Prot
ein
Ceramides
SPT
AIC
D
š¾-s
ecre
tase
Aš½š½-CTF
Aš½ degradation and clear
ance
Toxic oligomersGM1
nSM
ase
Ceramides
Cell death
Sphingosin-1-P
Aš½
Aš½
Aš½ Aš½
Oligomerizatio
n
Sphingomyelin
Via ApoESulfatides
stabi
lity
š½-s
ecre
tase
sAPP
š¼
sAPP
š½
Figure 2: Schematic illustration of the effects of sphingolipids and glycosphingolipids on APP processing. Interestingly, APP processingin return affects the metabolic pathways of sphingolipids. For example, it has been shown that AICD regulates the sphingolipid de novosynthesis by decreasing the expression of the Serinepalmitoyl-CoA-Transferase (SPT) or that Aš½ itself directly increases the activity of thesphingomyelin degrading enzyme Sphingomyelinase (SMase), resulting in complex regulatory cycles which are dysregulated in the case ofAlzheimerās disease.
Aš½ toxicity is linked to Cer-dependent apoptotic pathways.Lee et al. observed an Aš½-induced elevation of nSMase andconsequently increased Cer levels which resulted in remark-able cell death. Inhibiting this pathway abolished the Aš½-triggered cascade [140]. In this context, activation of nSMaseby Aš½42 but not Aš½40 has been reported [66, 141] (Figure 2).Recently, a potential novel mechanism of ceramide-enrichedexosomes released by Aš½-treated astrocytes was proposed tobe responsible for Aš½-induced apoptosis. Thereby, nSMase2was essential for charging these exosomes with Cer [142,143]. Beside the involvement of Cer in Aš½ toxicity, Cer hasbeen shown to alter APP processing and Aš½ production.Increasing Cer levels by either direct Cer administration orstimulation of endogenous biosynthesis by nSMase resultedin enhanced Aš½ production. Elevated Aš½ levels are attributedto Cer-induced protein stabilization of š½-secretase BACE1,whereas š¾-secretase is not affected [144]. Further studieselucidated the underlying mechanism of increased BACE1stability: elevated Cer level caused upregulation of the acetyl-transferases, ATase1, and ATase2, acetylating BACE1 proteinand thus protecting the nascent protein from degradation[145]. Taken together, it seems likely that Cer is the drivingforce in a circulus vitiosus: increasing Cer levels lead to anintensified Aš½ production whereupon Aš½ is responsible forCer accumulation.
Noteworthy in this context, S1P is discussed as a possiblecounterpart. S1P is considered to be neuroprotective andimportant for neuronal differentiation [146, 147]. Remark-ably, one study reported reduced S1P levels in frontotemporal
grey matter of AD patients [131], which implicates a possiblerole in AD. However, recent findings reported an increasedproteolytic activity of BACE1 by direct interaction withS1P [148]. Therefore, additional studies addressing S1P areimportant to clarify the significance of S1P in APP processingand AD.
4.2. Sphingomyelin. Sphingomyelin is an important compo-nent of mammalian cell membranes, particularly enrichedin myelin sheets and especially represented in the brain[149]. Considering the observations outlined in the preced-ing chapter it is suggested that SM concentrations in ADbrains might be decreased. Analysis of postmortem brain,however, show inconsistent results. Although two studiesreported elevated SM levels in AD brains compared to age-related controls [150, 151], two studies described a signif-icant decrease [131, 132]. Further studies only revealed amodest reduction in severe AD postmortem brains and nosignificant differences in earlier stages of the disease [125].Moreover, recent investigations found increased SM levels inthe cerebrospinal fluid (CSF) of individuals suffering fromprodromal AD, whereas there was only a slight but notsignificant decrease in mild and moderate AD groups [152].Interestingly, a current epidemiological study correlatedhigher plasma SM levels with slower cognitive decline amongAD patients, illustrating SM as potential sensitive blood-based biomarker for disease progression [153]. Importantly,nSMase was reported to be upregulated in AD brains [133],
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resulting in increased SM breakdown. Additionally, in cellculture studies, nSMase activity is known to be elevated inpresenilin familial Alzheimerās disease mutations (PS-FAD)causing early onset AD [66], pointing towards a possiblerole of SMases in sporadic late onset as well as in familialearly onset AD pathology. Interestingly, SM itself is discussedto alter APP processing. Increasing SM by either directtreatment of cells with SM or inhibition of nSMase resultedin diminished Aš½ levels [66]. In this context, it is again worthmentioning that Aš½42 itself regulates SM homeostasis asdescribed previously.
4.3. Gangliosides. Gangliosides are a family of sialic acidcontaining glycosphingolipids, highly expressed in neuronaland glial membranes, where they play important roles fordevelopment, proliferation, differentiation, and maintenanceof neuronal tissues and cells [154, 155]. The first step towardsthe formation of gangliosides is the glycosylation of Cerby glucosylceramide-synthase (GCS). According to theirnumber of sialic acid residues, gangliosides are separated infour different ganglio-series: o-series, a-series, b-series, andc-series. Importantly, the most common brain gangliosidesbelong either to the a-series (GM1 and GD1a) or b-series(GD1b and GT1b).The ganglioside GM3 serves as a commonprecursor for a- and b-series gangliosides.TheGD3-synthase(GD3S) catalyzes the synthesis of GD3 by adding sialic acid toGM3, segregating the a- and b-series of gangliosides [156] andtherefore controlling the levels of the major brain ganglio-sides. Gangliosides are also able to interact with furthermem-brane lipids like SM and cholesterol, thereby, being involvedin the formation of lipid rafts [157]. Interestingly, postmortemstudies of AD brains suggest a strong connection betweenganglioside homeostasis and AD pathology. In a previouswork, Kracun et al. found all major brain gangliosides to bereduced in the temporal and frontal cortex and in nucleusbasalis of Meynert, whereas simple gangliosides GM2 andGM3 were elevated in parietal and frontal cortex [158]. GM3elevation was further supported by a recent study. Here, theauthors also described an increase in glucosylceramide levels,the precursor for ganglioside synthesis [159]. Additionally,Gottfries et al. reported a significant reduction of gangliosidesin the grey matter of early onset AD subjects comparedto late onset AD and control individuals. Nevertheless, adecrease in total gangliosides was also observed in brainsof late onset AD patients, however, to a smaller extent[160]. A more recent study found elevated levels of GM1and GM2 in lipid raft fractions of the temporal and frontalcortex of AD brains [161]. Moreover, the analysis of ADtransgenic mouse models suggests an altered gangliosidemetabolism in AD. Barrier et al. compared different trans-genic mice with age-matched wildtype controls. While allmice expressing APP (SL) showed an increase in GM2 andGM3 in the cerebral cortex and a moderate decrease incomplex b-series gangliosides, only APP/PS1Ki transgenicmice exhibited a loss of complex a-series gangliosides, GT1a,GD1a, and GM1 [162]. In summary, ganglioside metabolismseems to be highly affected during disease progression.Whilemore complex gangliosides appear to be depleted, simplegangliosides, like GM1 andGM3 are increased. Asmentioned
previously GM3 is an important precursor for a- and b-seriesgangliosides suggesting a disease-dependent alteration in thebiosynthesis of these ganglioside series. Indeed, we found aclose link between APP processing products and gangliosidemetabolism.The activity of GD3S, the key enzyme convertinga- to b-series gangliosides, is significantly reduced by twoseparate and additive mechanisms. On one hand, GD3Sactivity is inhibited by the binding of Aš½ peptides to GM3,consequently reducing substrate availability and preventingthe conversion of GM3 to GD3. On the other hand, genetranscription of GD3S is downregulated and mediated by theAPP intracellular domain (AICD), thus, resulting in GD3depletion and GM3 accumulation [163].
Furthermore, especially GM1 is related to several AD-specific pathomechanisms like altered APP processing,aggregation, and cytotoxicity. GM1 was found to decreasesAPPš¼ levels and to increase Aš½ generation, whereassAPPš½ levels were unchanged [164]. This suggests increasedš¾-secretase and decreased š¼-secretase activities withoutaffecting š½-secretase. Indeed, as recently described, thedirect administration of gangliosides to purified š¾-secretaseresulted in an increased enzyme activity. Moreover, a shifttowards the formation of Aš½42 peptides was observed [165].Interestingly, Aš½ decreases membrane fluidity by bindingGM1. As a consequence, amyloidogenic APP processingwas stimulated, proposing an Aš½-triggered, GM1-mediated,vicious cycle [166]. Further mechanisms linking ganglio-sides to Aš½ production were described by Tamboli et al.Inhibition of GCS, the committed step towards gangliosideformation, significantly decreased Aš½ formation. An alteredAPP maturation and cell surface transport, leading to lessaccess of APP to amyloidogenic processing in the endosomalcompartments, were proposed as the underlyingmechanisms[167].
Furthermore, GM1 seems to be particularly importantas a āseedā for amyloid plaque formation. Thereby, GM1interacts with Aš½, resulting in GAš½ complexes [168]. Thiscomplex tends to aggregate more easily due to changing thesecondary structure of Aš½ towards š½-sheet formation [169,170]. Interestingly, Mahfoud et al. described a sphingolipidbinding domain of Aš½, which is also contained in HIV-1 and prion proteins [171]. Further investigations displayedaccumulation and aggregation of Aš½ on cell membranesespecially in GM1-enriched lipid rafts, resulting in enhancedcytotoxicity [172, 173]. Additionally, enhanced cytotoxicity ofAš½ fibrils was observed after release of GM1 from damagedneurons, indicating a possible aggravation mechanism [174].Importantly, GAš½ complexes also occur in AD brains andaged mice [175]. Synaptosomes, prepared from aged mousebrains, exhibited GM1 clusters, showing high ability toinitiate Aš½ aggregation [176]. Remarkably, Aš½ depositionwas observed to begin mainly at the presynaptic neuronalmembranes in AD brains, suggesting a possible role of GAš½in the early pathogenesis of AD [177, 178].
4.4. Sulfatides. Another sphingolipid subgroup, possiblyinvolved in AD pathogenesis, are sulfatides. They are gener-ated from Cer by adding a galactose moiety, catalyzed by theceramide galactosyltransferase (CGT). Finally, synthesis of
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sulfatides is provided by cerebroside sulfotransferase (CST),which transfers a sulfate group to the galactosyl moiety. Thedegradation of sulfatides takes place in the lysosomal com-partment, where arylsulfatase A (ASA) hydrolyzes the sulfategroup. ASA deficiency leads to accumulation of sulfatidesand to the clinical picture of metachromatic leukodystrophy.Sulfatides are especially enriched in myelin sheaths makingup about 5% of the myelin lipids. Hence, they are particularlyproduced by oligodendrocytes and Schwann cells. Never-theless, sulfatides have also been detected in neurons andastrocytes, however, in a lower amount [179]. Interestingly,AD pathology is known to induce focal demyelination anddegeneration of oligodendrocytes [180].
Importantly, Han et al. described an extraordinary deple-tion of sulfatide levels in all analyzed brain regions of ADsubjects. Sulfatides were depleted up to 93% in grey matterand up to 58% in white matter.These alterations were alreadyobserved in the earliest stages of the disease [125]. Addition-ally, a previous study found decreased sulfatide levels in thewhite matter of the frontal lobe only in patients with lateonset AD compared to age-matched controls and early onsetADpatients [160]. Furthermore, Bandaru et al. also describeddecreased sulfatide content in the white matter; however,they did not confirm the alterations in the grey matter [150].In contrast, further studies found no significant changesbetween control andADbrains [132, 159].Worthmentioning,a 40% reduction in CSF sulfatide levels was detected amongAD patients. In this context, sulfatide/phosphatidylinositolratio was proposed as potential clinical biomarker for earlyAD diagnosis [181]. However, data obtained by analyzingtransgenic mouse models in respect to alterations in sulfatidelevels are more inconsistent. Although Barrier et al. foundno significant changes between wildtype mice and doubletransgenic APPSL/PS1Ki mice or single-transgenic PS1Kimice [135], a more recent study found significantly decreasedsulfatide levels in the forebrain of these mouse models[159].
Noteworthy, there is a possible link between sulfatidehomeostasis and ApoE trafficking. First, the intercellular sul-fatide transport in the brain is mediated by ApoE-containinglipoproteins. Interestingly, humanApoE4 carrying transgenicmice presented the highest sulfatide depletion in the brain incomparison to wildtype ApoE or human ApoE3 transgenicmice [181]. Furthermore, a recent study showed a significant,age-related decrease of sulfatides in APP transgenic mice,which was completely abolished by ApoE knockout [182].These findings offer a possible explanation for decreased sul-fatide levels in AD brains. On the other hand, sulfatides seemto be involved in the ApoE-dependent Aš½ clearance. Directsupplementation of sulfatides to cultured cells dramaticallyreduced Aš½ levels. This observation was most likely ascribedto a modification of Aš½ clearance through an endocytoticpathway. Thereby, sulfatides facilitated the ApoE-mediatedAš½ clearance, especially of ApoE4 containing vesicles [183].Nevertheless, the importance of sulfatide-dependent molec-ular mechanisms, being involved in AD pathogenesis, is stillambiguous.Therefore, further investigations are necessary toclarify the role of sulfatides in APP processing and AD.
5. Lipids and Tau Pathology
Beside amyloid plaques, neurofibrillary tangles (NFTs), con-sisting of hyperphosphorylated tau proteins, are consideredto be a pivotal pathological hallmark of AD [184ā186].Although this review focuses on the impact of lipids on APPprocessing, it is worth mentioning that tau pathology is alsoaffected by an altered lipid homeostasis. Tau proteins belongto the family of microtubule-associated proteins, importantfor the assembly of tubulin monomers into microtubules, tostabilize the neuronal microtubule network which is essentialfor maintaining cell shape and axonal transport [187]. InAD, this function is disrupted, due to the hyperphospho-rylation of serine/threonine residues of tau. This abnormalphosphorylation promotes the release of tau proteins frommicrotubules, its disassembly, and self-assembly into pairedhelical filaments (PHFs), a major component of NFTs, and,as a consequence, provokes microtubule disruption [188ā191]. Supporting the connection between lipids and tau,Kawarabayashi et al. reported an accumulation of phosphory-lated tau in brain-extracted lipid rafts of an ADmouse model[192]. In addition, tau phosphorylation by cyclin-dependentkinase 5 (CDK5) was observed in lipid rafts after short-term incubation of SH-SY5Y cells with Aš½ peptides [193].Interestingly, Niemann-Pick type C (NPC), an inheritedlysosomal storage disease with an abnormal intracellularaccumulation of cholesterol, also exhibits tau pathology [194,195]. Noteworthy, these alterations are more pronounced inneurons containing higher cholesterol levels [194, 196]. Inline with these findings elevated Aš½ and total tau levelswere observed in the cerebrospinal fluid of NPC patients[197]. In an NPC mouse model, Sawamura et al. illustrateda possible explanation for these hyperphosphorylated tauforms. They found an intensified activation of the mitogen-activated protein kinase (MAPK)-pathway, one of severalkinases phosphorylating tau physiologically in the brain[198]. Not only in NPCmodel mice but also in further mousemodels, the cholesterol and ApoE status were associated withincreased tau phosphorylation [199ā201]. In contrast, statintreatment reduced NFT burden in normocholesterolemicand hypercholesterolemic mice. This effect, however, wasrather attributed to the anti-inflammatory properties thanto the cholesterol lowering aspect of statins [202]. Addition-ally, simvastatin treatment of hypercholesterolemic subjectswithout dementia revealed a significant phospho-tau-181decrease in the CSF, whereas no differences in total tauor Aš½ levels were observed [203]. Importantly, membranecholesterol levels are closely linked to theAš½-induced calpainactivation and tau toxicity [204]. Calpain is a calcium-dependent cysteine protease responsible for the generation ofthe neurotoxic 17 kDa tau [205, 206]. Decreasing membranecholesterol in mature neurons reduced their susceptibility tothe Aš½-induced calpain activation, 17 kDa tau production,and cell death, whereas elevated membrane cholesterol lev-els enhanced this Aš½-triggered cascade in young neurons[204]. Like calpain, AMP-activated protein kinase (AMPK),a serine/threonine kinase, is also activated by elevated cal-cium levels. Interestingly, in addition to its important func-tion in regulating cholesterol homeostasis, emerging studies
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revealed AMPK as a potential tau phosphorylating enzyme[207, 208]. AMPK-induced abnormal tau phosphorylationinhibited microtubule binding of tau [207]. In line withthese findings Vingtdeux et al. reported an accumulation ofactivated AMPK in cerebral neurons of AD brains [209].Other authors, however, even ascribed AMPK an inhibitingfunction in tau phosphorylation by downregulating glycogensynthase kinase-3š½ (GSK3š½) activity, one of the main tauphosphorylating kinases [210, 211]. Beside cholesterol, š-3fatty acids are also discussed to influence tau pathology. In a3xTg-AD mouse model, Green et al. demonstrated loweredlevels of intraneuronal tau and reduced tau phosphoryla-tion after 3 to 9 months of DHA supplementation [112].Similar results were also observed by Ma et al. after fishoil administration to 3xTg-AD mice [212]. In both studies,the reduced phosphorylation was attributed to an inhibitionof the c-Jun N-terminal kinase (JNK). In contrast, low š3intake with a decreased š3 :š6 ratio leads to an aggravationof tau pathology in these transgenic mice [213]. Further-more, some studies revealed a colocalization of sphingolipidsand gangliosides with PHFs proposing a possible relationbetween sphingolipid metabolism and tau [214, 215]. Indeed,inhibition of the serine palmitoyl transferase (SPT), therate-limiting enzyme in sphingolipid synthesis, and the firststep towards ceramide synthesis resulted in a reduced tauhyperphosphorylation in an AD mouse model [216]. Aftertreatment of differentiated PC12 cells with ceramide derivates(N-acetylsphingosine, and N-hexanoylsphingosine), Xie andJohnson reported a significant reduction in tau levels withoutaffecting tau phosphorylation. This was attributed to anincreased expression of calpain I and thus stimulated tauprotein degradation [217]. Taken together, not only APPprocessing but also tau pathology is influenced by lipids.Although the general view for APP processing seems moreconsistent, further investigations linking tau to altered lipidhomeostasis should follow.
6. Conclusion
Summing it up, lipids are tightly linked to AD. It has beenshown that cholesterol increases amyloidogenic pathwaysand decreases non amyloidogenic pathways followed by anenhanced Aš½ production and aggregation. Opposite effectswere observed for DHA, suggesting a potential beneficialrole for DHA or PUFAs in AD. For sphingolipids and gly-cosphingolipids, a more complex situation in respect to ADis reported. Although lipids like SM, S1P, and sulfatides seemto be protective by enhancing Aš½ clearance or decreasingAš½ production, other glycosphingolipids like gangliosides orceramides increase Aš½ toxicity or Aš½ oligomerization. Inter-estingly, it has been shown that, in return, APP processingalso affects lipid metabolism, resulting in complex regulatoryfeed-back cycles, which seem to be dysregulated in AD.In line, several studies suggest an altered lipid metabolismin human AD brains. However, controversial effects arereported in different brain regions and tissues, making moredetailed analysis with new lipidomic approaches and highernumbers necessary.
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