Deposition of the β-amyloid (Aβ) peptide is thought to underlie development of Alzheimer's disease (AD). This pathological linkage has spurred considerable interest in therapeutic strategies to reduce Aβ production. It is becoming increasingly clear that altered cholesterol homeostasis can modulate Aβ production and/or accumulation. In this review, we discuss the molecular pathology of AD, the cholesterol connection and recent data suggesting that the oxysterol receptor, liver X receptor LXR (NR1H2 and NR1H3), may modulate these events.
References
1.
BogdanovicN., BretillonL., LundE. G., DiczfalusyU., LannfeltL., WinbladB., RussellD. W., and BjorkhemI. (2001). On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cellsNeurosci Lett314, 45–8.
2.
BouillotC., ProchiantzA., RougonG., and AllinquantB. (1996). Axonal amyloid precursor protein expressed by neurons in vitro is present in a membrane fraction with caveolae-like propertiesJ Biol Chem271, 7640–4.
3.
BurnsM., GaynorK., OlmV., MerckenM., LaFrancoisJ., WangL., MathewsP. M., NobleW., MatsuokaY., and DuffK. (2003). Presenilin redistribution associated with aberrant cholesterol transport enhances β-amyloid production in vivoJ Neurosci23, 5645–9.
4.
CaoG., BeyerT. P., YangX. P., SchmidtR. J., ZhangY., BenschW. R., KauffmanR. F., GaoH., RyanT. P., LiangY., EachoP. I., and JiangX. C. (2002). Phospholipid transfer protein is regulated by liver X receptors in vivoJ Biol Chem277, 39561–5.
5.
CorderE. H., SaundersA. M., StrittmatterW. J., SchmechelD. E., GaskellP. C., SmallG. W., RosesA. D., HainesJ. L., and Pericak-VanceM. A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset familiesScience261, 921–3.
6.
DanikM., ChampagneD., Petit-TurcotteC., BeffertU., and PoirierJ. (1999). Brain lipoprotein metabolism and its relation to neurodegenerative diseaseCrit Rev Neurobiol13, 357–407.
7.
EhehaltR., KellerP., HaassC., ThieleC., and SimonsK. (2003). Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid raftsJ Cell Biol160, 113–23.
8.
FassbenderK., SimonsM., BergmannC., StroickM., LutjohannD., KellerP., RunzH., KuhlS., BertschT., von BergmannK., HennericiM., BeyreutherK., and HartmannT. (2001). Simvastatin strongly reduces levels of Alzheimer's disease β -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivoProc Natl Acad Sci U S A98, 5856–61.
9.
FukumotoH., DengA., IrizarryM. C., FitzgeraldM. L., and RebeckG. W. (2002). Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Abeta levelsJ Biol Chem277, 48508–13.
10.
HardyJ., and SelkoeD. J. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeuticsScience297, 353–6.
11.
HebertL. E., ScherrP. A., BieniasJ. L., BennettD. A., and EvansD. A. (2003). Alzheimer disease in the US population: prevalence estimates using the 2000 censusArch Neurol60, 1119–22.
12.
JickH., ZornbergG. L., JickS. S., SeshadriS., and DrachmanD. A. (2000). Statins and the risk of dementiaLancet356, 1627–31.
13.
JosephS. B., and TontonozP. (2003). LXRs: new therapeutic targets in atherosclerosis?Curr Opin Pharmacol3, 192–7.
14.
JosephS. B., McKilliginE., PeiL., WatsonM. A., CollinsA. R., LaffitteB. A., ChenM., NohG., GoodmanJ., HaggerG. N., TranJ., TippinT. K., WangX., LusisA. J., HsuehW. A., LawR. E., CollinsJ. L., WillsonT. M., and TontonozP. (2002). Synthetic LXR ligand inhibits the development of atherosclerosis in miceProc Natl Acad Sci U S A99, 7604–9.
15.
KinoshitaA., FukumotoH., ShahT., WhelanC. M., IrizarryM. C., and HymanB. T. (2003). Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomesJ Cell Sci116, 3339–46.
16.
KochS., DonarskiN., GoetzeK., KreckelM., StuerenburgH. J., BuhmannC., and BeisiegelU. (2001). Characterization of four lipoprotein classes in human cerebrospinal fluidJ Lipid Res42, 1143–51.
17.
KojroE., GimplG., LammichS., MarzW., and FahrenholzF. (2001). Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α -secretase ADAM 10Proc Natl Acad Sci U S A98, 5815–20.
18.
KoldamovaR. P., LefterovI. M., IkonomovicM. D., SkokoJ., LefterovP. I., IsanskiB. A., DeKoskyS. T., and LazoJ. S. (2003). 22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid β secretionJ Biol Chem278, 13244–56.
19.
Le LayS., RobichonC., Le LiepvreX., DagherG., FerreP., and DugailI. (2003). Regulation of ABCA1 expression and cholesterol efflux during adipose differentiation of 3T3-L1 cellsJ Lipid Res44, 1499–507.
20.
LiangY., LinS., BeyerT. P., ZhangY., WuX., BalesK. R., DeMattosR. B., MayP. C., LiS. D., JiangX. C., EachoP. I., CaoG., and PaulS. M. (2004). A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytesJ Neurochem88, 623–34.
21.
LundE. G., XieC., KottiT., TurleyS. D., DietschyJ. M., and RussellD. W. (2003). Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnoverJ Biol Chem278, 22980–8.
22.
MarlowL., CainM., PappollaM. A., and SambamurtiK. (2003). β-secretase processing of the Alzheimer's amyloid protein precursor (APP)J Mol Neurosci20, 233–9.
23.
MassonD., StaelsB., GautierT., DesrumauxC., AthiasA., Le GuernN., SchneiderM., ZakZ., DumontL., DeckertV., TallA., JiangX. C., and LagrostL. (2004). Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouseJ Lipid Res45, 543–50.
24.
MastersC. L., SimmsG., WeinmanN. A., MulthaupG., McDonaldB. L., and BeyreutherK. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndromeProc Natl Acad Sci U S A82, 4245–9.
25.
PasternakS. H., BagshawR. D., GuiralM., ZhangS., AckerleyC. A., PakB. J., CallahanJ. W., and MahuranD. J. (2003). Presenilin-1, nicastrin, amyloid precursor protein, and γ-secretase activity are co-localized in the lysosomal membraneJ Biol Chem278, 26687–94.
26.
PloschT., KokT., BloksV. W., SmitM. J., HavingaR., ChiminiG., GroenA. K., and KuipersF. (2002). Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1J Biol Chem277, 33870–7.
27.
RefoloL. M., MalesterB., LaFrancoisJ., Bryant-ThomasT., WangR., TintG. S., SambamurtiK., DuffK., and PappollaM. A. (2000). Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse modelNeurobiol Dis7, 321–31.
28.
RiddellD. R., ChristieG., HussainI., and DingwallC. (2001). Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid raftsCurr Biol11, 1288–93.
29.
RunzH., RietdorfJ., TomicI., de BernardM., BeyreutherK., PepperkokR., and HartmannT. (2002). Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cellsJ Neurosci22, 1679–89.
30.
SchroederF., GallegosA. M., AtshavesB. P., StoreyS. M., McIntoshA. L., PetrescuA. D., HuangH., StarodubO., ChaoH., YangH., FrolovA., and KierA. B. (2001). Recent advances in membrane microdomains: rafts, caveolae, and intracellular cholesterol traffickingExp Biol Med (Maywood)226, 873–90.
31.
SchultzJ. R., TuH., LukA., RepaJ. J., MedinaJ. C., LiL., SchwendnerS., WangS., ThoolenM., MangelsdorfD. J., LustigK. D., and ShanB. (2000). Role of LXRs in control of lipogenesisGenes Dev14, 2831–8.
32.
SimanR., and VeljiJ. (2003). Localization of presenilin-nicastrin complexes and γ-secretase activity to the trans-Golgi networkJ Neurochem84, 1143–53.
33.
SimonsM., KellerP., De StrooperB., BeyreutherK., DottiC. G., and SimonsK. (1998). Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neuronsProc Natl Acad Sci U S A95, 6460–4.
34.
SparksD. L. (1996). Intraneuronal β-amyloid immunoreactivity in the CNSNeurobiol Aging17, 291–9.
35.
SparksD. L., LiuH., ScheffS. W., CoyneC. M., and HunsakerJ. C.3rd (1993). Temporal sequence of plaque formation in the cerebral cortex of non-demented individualsJ Neuropathol Exp Neurol52, 135–42.
36.
SunY., YaoJ., KimT. W., and TallA. R. (2003). Expression of liver X receptor target genes decreases cellular amyloid β peptide secretionJ Biol Chem278, 27688–94.
37.
VaughanA. M., and OramJ. F. (2003). ABCA1 redistributes membrane cholesterol independent of apolipoprotein interactionsJ Lipid Res44, 1373–80.
38.
WahrleS., DasP., NyborgA. C., McLendonC., ShojiM., KawarabayashiT., YounkinL. H., YounkinS. G., and GoldeT. E. (2002). Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomainsNeurobiol Dis9, 11–23.
39.
WhitneyK. D., WatsonM. A., CollinsJ. L., BensonW. G., StoneT. M., NumerickM. J., TippinT. K., WilsonJ. G., WinegarD. A., and KliewerS. A. (2002). Regulation of cholesterol homeostasis by the liver X receptors in the central nervous systemMol Endocrinol16, 1378–85.
40.
WilliamsK. R., SaundersA. M., RosesA. D., and ArmatiP. J. (1998). Uptake and internalization of exogenous apolipoprotein E3 by cultured human central nervous system neuronsNeurobiol Dis5, 271–9.
41.
WolozinB., KellmanW., RuosseauP., CelesiaG. G., and SiegelG. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitorsArch Neurol57, 1439–43.
42.
WongC. W., QuarantaV., and GlennerG. G. (1985). Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically relatedProc Natl Acad Sci U S A82, 8729–32.
43.
YuL., YorkJ., von BergmannK., LutjohannD., CohenJ. C., and HobbsH. H. (2003). Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8J Biol Chem278, 15565–70.
44.
ZhangM., DwyerN. K., NeufeldE. B., LoveD. C., CooneyA., ComlyM., PatelS., WatariH., StraussJ. F.3rd, PentchevP. G., HanoverJ. A., and Blanchette-MackieE. J. (2001). Sterol-modulated glycolipid sorting occurs in niemann-pick C1 late endosomesJ Biol Chem276, 3417–25.