Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.

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Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM.

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1(-/-) mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe(-/-) mice: there was significantly less amyloid beta-peptide (Abeta) deposition, a redistribution of Abeta to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.
PMID: 18202749 [PubMed - indexed for MEDLINE]
PMCID: PMC2200302

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C-terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65.

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Lakshmana MK, Chen E, Yoon IS, Kang DE.

Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid beta protein (Abeta), a small peptide derived from beta- and gamma-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that the Low-density lipoprotein receptor-related protein (LRP) plays a pivotal role in the trafficking of APP and generation of Abeta. In particular, we recently showed that the soluble cytoplasmic tail of LRP (LRP-ST) without a membrane tether was sufficient to promote Abeta generation. In this study, we demonstrate that the last 37 residues of LRP cytoplasmic tail (LRP-C37) lacking the NPxY motifs and FE65 binding mediate the core pro-amyloidogenic activity of LRP-ST. Moreover, we show that the conserved dileucine motif within the LRP-C37 region is a key determinant of its Abeta promoting activity. Finally, results from a yeast 2-hybrid screen using LRP-C37 region as bait reveal 4 new LRP-binding proteins implicated in intracellular signaling and membrane protein trafficking. Our findings indicate that the LRP-C37 sequence represents a new protein-binding domain that may be useful as a therapeutic target and tool to lower Abeta generation in AD.
PMID: 18373737 [PubMed - as supplied by publisher]



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Plasma membrane expression of the neuronal glutamate transporter EAAC1 is regulated by glial factors: Evidence for different regulatory pathways assoc

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Lortet S, Canolle B, Masmejean F, Nieoullon A.

IC2N-IBDML, UMR CNRS 6216, Parc Scientifique et Technologique de Luminy, Case 907, 13288 Marseille Cedex 09, France.

At the glutamatergic synapse the neurotransmitter is removed from the synaptic cleft by high affinity amino acid transporters located on neurons (EAAC1) and astrocytes (GLAST and GLT1), and a coordinated action of these cells is necessary in order to regulate glutamate extracellular concentration. We show here that treatment of neuronal cultures with glial soluble factors (GCM) is associated with a redistribution of EAAC1 and GLAST to the cell membrane and we analysed the effect of membrane cholesterol depletion on this regulation. In enriched neuronal culture (90% neurons and 10% astrocytes), GCM treatment for 10 days increases EAAC1 and GLAST cell surface expression with no change in total expression. In opposite, GLT1 surface expression is not modified by GCM but total expression is increased. When cholesterol is acutely depleted from the membrane by 10mM methyl-beta-cyclodextrin (beta5-MCD, 30min), glutamate transport activity and cell surface expressions of EAAC1 and GLAST are decreased in the enriched neuronal culture treated by GCM. In pure neuronal culture addition of GCM also increases EAAC1 cell membrane expression but surprisingly acute treatment with beta5-MCD decreases glutamate uptake activity but not EAAC1 cell membrane expression. By immunocytochemistry a modification in the distribution of EAAC1 within neurons was undetectable whatever the treatment but we show that EAAC1 was no more co localized with Thy-1 in the enriched neuronal culture treated by GCM suggesting that GCM have stimulated polarity formation in neurons, an index of maturation. In conclusion we suggest that different regulatory mechanisms are involved after GCM treatment, glutamate transporter trafficking to and from the plasma membrane in enriched neuronal culture and modulation of EAAC1 intrinsic activity and/or association with regulatory proteins at the cell membrane in the pure neuronal culture. These different regulatory pathways of EAAC1 are associated with different neuronal maturation stages.
PMID: 18400334 [PubMed - in process]

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Discrete roles of apoA-I and apoE in the biogenesis of HDL species: lessons learned from gene transfer studies in different mouse models.

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Zannis VI, Koukos G, Drosatos K, Vezeridis A, Zanni EE, Kypreos KE, Chroni A.

Molecular Genetics, Whitaker Cardiovascular Institute, Departments of Medicine and Biochemistry, Boston University School of Medicine, Boston, MA 02118-2394, USA. vzannis@bu.edu

Using adenovirus-mediated gene transfer in apolipoprotein A-I (apoA-I)-deficient mice, we have established that apoA-I mutations inhibit discrete steps in a pathway that leads to the biogenesis and remodeling of high-density lipoprotein (HDL). To this point, five discrete categories of apoA-I mutants have been characterized that may affect the interactions of apoA-I with ATP-binding cassette superfamily A, member 1 (ABCA1) or lecithin:cholesterol acyl transferase (LCAT) or may influence the plasma phospholipid transfer protein activity or may cause various forms of dyslipidemia. Biogenesis of HDL is not a unique property of apoA-I. Using adenovirus-mediated gene transfer of apoE in apoA-I- or ABCA1-deficient mice, we have established that apolipoprotein E (apoE) also participates in a novel pathway of biogenesis of apoE-containing HDL particles. This process requires the functions of the ABCA1 lipid transporter and LCAT, and it is promoted by substitution of hydrophobic residues in the 261 to 269 region of apoE by Ala. The apoE-containing HDL particles formed in the circulation may have atheroprotective properties. ApoE-containing HDL may also have important biological functions in the brain that confer protection from Alzheimer's disease.
PMID: 18246469 [PubMed - in process]

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Cholesterol and Clioquinol modulation of A beta(1-42) interaction with phospholipid bilayers and metals.

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Lau TL, Gehman JD, Wade JD, Masters CL, Barnham KJ, Separovic F.

School of Chemistry, Bio21 Institute, The University of Melbourne, Victoria 3010, Australia.

The beta-sheet plaques that are the most obvious pathological feature of Alzheimer's disease are composed of amyloid-beta peptides and are highly enriched in the metal ions Zn, Fe and Cu. The interaction of the full-length amyloid peptide, A beta(1-42), with phospholipid lipid bilayers was studied in the presence of the metal-chelating drug, Clioquinol (CQ). The effect of cholesterol and metal ions was also determined using solid-state 31P and 2H NMR. CQ modulated the effect of metal ions on the integrity of the bilayer and although CQ perturbed the phospholipid membrane, the bilayer integrity was maintained. Model membranes enriched in cholesterol were studied under conditions of peptide association and incorporation. Solid-state NMR showed that the bilayer integrity was preserved in cholesterol-enriched membranes in comparison to phosphatidylcholine-phosphatidylserine bilayers. Changes in peptide structure, consistent with an increase in beta-sheet, were observed using specifically 13C-labelled A beta(1-42) by magic angle spinning NMR. Results using aligned phosphatidylcholine bilayers and completely 15N-labelled peptide indicated that the peptide aggregated. The results are consistent with oligomeric beta-sheet structured peptides only partially penetrating the bilayer and cholesterol reducing the membrane disruption.
PMID: 17920561 [PubMed - indexed for MEDLINE]


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Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease.

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Zou F, Gopalraj RK, Lok J, Zhu H, Ling IF, Simpson JF, Tucker HM, Kelly JF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Bennett DA, Crook JE, Younkin SG, Estus S.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

Since apoE allele status is the predominant Alzheimer's disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNPs) in brain apoE receptors represent excellent candidates for association with AD. Recently, we identified a SNP, rs688, as modulating the splicing efficiency of low-density lipoprotein receptor (LDLR) exon 12 in female human liver and in minigene-transfected HepG2 cells. Moreover, the rs688T minor allele was associated with significantly higher LDL and total cholesterol in women within the Framingham Offspring Study cohort. Since LDLR is a major apoE receptor in the brain, we hypothesized that rs688 modulates LDLR splicing in neural tissues and associates with AD. To evaluate this hypothesis, we first transfected LDLR minigenes into SH-SY5Y neuroblastoma cells and found that the rs688T allele reduces exon 12 inclusion in this neural model. We then evaluated the association of rs688 allele with exon 12 splicing efficiency in vivo by quantifying LDLR splicing in human anterior cingulate tissue obtained at autopsy; the rs688T allele is associated with decreased LDLR exon 12 splicing efficiency in aged males, but not females. Lastly, we evaluated whether rs688 associates with AD by genotyping DNA from 1457 men and 2055 women drawn from three case-control series. The rs688T/T genotype was associated with increased AD odds in males [recessive model, odds ratio (OR) of 1.49, 95% confidence interval (CI) of 1.13-1.97, uncorrected P = 0.005], but not in females. In summary, these studies identify a functional apoE receptor SNP that is associated with AD in a sex-dependent fashion.
PMID: 18065781 [PubMed - indexed for MEDLINE]
PMCID: PMC2361153 [Available on 04/01/09]


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Interaction with amyloid Beta Peptide compromises the lipid binding function of apolipoprotein e.

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Tamamizu-Kato S, Cohen JK, Drake CB, Kosaraju MG, Drury J, Narayanaswami V.
vnarayan@chori.org.

Apolipoprotein (apo) E is an exchangeable apolipoprotein that plays an integral role in cholesterol transport in the plasma and the brain. It is also associated with protein misfolding or amyloid proteopathy of the beta amyloid peptide (Abeta) in Alzheimer's disease (AD) and cerebral amyloid angiopathy. The C-terminal domain (CT) of apoE encompasses two types of amphipathic alpha helices: a class A helix (residues 216-266) and a class G* helix (residues 273-299). This domain also harbors high-affinity lipoprotein binding and apoE self-association sites that possibly overlap. The objective of this study is to examine if the neurotoxic oligomeric Abeta interacts with apoE CT and if this association affects the lipoprotein binding function of recombinant human apoE CT. Site-specific fluorescence labeling of single cysteine-containing apoE CT variants with donor probes were employed to identify the binding of Abeta bearing an acceptor probe by intermolecular fluorescence resonance energy-transfer analysis. A higher efficiency of energy transfer was noted with probes located in the class A helix than with those located in the class G* helix of apoE CT. In addition, incubation of apoE CT with Abeta severely impaired the lipid binding ability and the overall amount of lipid-associated apoE CT. However, when apoE CT is present in a lipid-bound state, Abeta appears to be localized within the lipid milieu of the lipoprotein particle and not associated with any specific segments of the protein. When our data are taken together, they suggest that Abeta association compromises the fundamental lipoprotein binding function of apoE, which may have implications not only in terms of amyloid buildup but also in terms of the accumulation of cholesterol at extracellular sites.
PMID: 18407659 [PubMed - in process]


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HIGH CHOLESTEROL-INDUCED NEUROINFLAMMATION AND AMYLOID PRECURSOR PROTEIN PROCESSING CORRELATE WITH LOSS OF WORKING MEMORY IN MICE.

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Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, Bhat NR.
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer's disease (AD)-like dementia but the underlying mechanisms remain unknown. In this study, we evaluated the cognitive performance in rodent models of hypercholesterolemia in relation to neuroinflammatory changes and amyloid precursor protein (APP) processing, the two key parameters of AD pathogenesis. Groups of normal C57BL/6 and low density lipoprotein receptor (LDLR)-deficient mice were fed a high fat/cholesterol diet for an 8-week period and tested for memory in a radial arm maze. It was found that the C57BL/6 mice receiving a high fat diet were deficient in handling an increasing working memory (WM) load compared to counterparts receiving a control diet while the hypercholesterolemic LDLR-/- mice showed impaired WM regardless of diet. Immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampi from high fat-fed C57BL/6 mice and LDLR-/- mice. Consistent with a neuroinflammatory response, the hyperlipidemic mice showed increased expression of cytokines/mediators including TNFalpha, IL-1beta, IL-6, NOS2 and COX2. There was also an induced expression of the key APP processing enzyme i.e., BACE1 in both high fat/cholesterol-fed C57BL/6 and LDLR-/- mice accompanied by an increased generation of C-terminal fragments (CTFs) of APP. Although ELISA for Abeta failed to record significant changes in the non-transgenic mice, a 3-fold increase in Abeta-40 accumulation was apparent in a strain of transgenic mice expressing wt hAPP on high fat/cholesterol diet. The findings link hypercholesterolemia with cognitive dysfunction potentially mediated by increased neuroinflammation and APP processing in a non-transgenic mouse model.
PMID: 18410513 [PubMed - as supplied by publisher]

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Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in nor

Shea TB.
Center for Cellular Neurobiology & Neurodegeneration Research, University of Massachusetts Lowell, Lowell, MA 01854, USA. Thomas_shea@uml.edu
In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.
PMID: 17914184 [PubMed - indexed for MEDLINE]


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Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's disease (AD):

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Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM.

Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM.
Department of Medicine, University of California, Los Angeles, California 90095, USA.
Environmental and genetic factors, notably ApoE4, contribute to the etiology of late-onset Alzheimer's disease (LOAD). Reduced mRNA and protein for an apolipoprotein E (ApoE) receptor family member, SorLA (LR11) has been found in LOAD but not early-onset AD, suggesting that LR11 loss is not secondary to pathology. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate beta-amyloid (Abeta). Genetic polymorphisms that reduce LR11 expression are associated with increased AD risk. However these polymorphisms account for only a fraction of cases with LR11 deficits, suggesting involvement of environmental factors. Because lipoprotein receptors are typically lipid-regulated, we postulated that LR11 is regulated by docosahexaenoic acid (DHA), an essential omega-3 fatty acid related to reduced AD risk and reduced Abeta accumulation. In this study, we report that DHA significantly increases LR11 in multiple systems, including primary rat neurons, aged non-Tg mice and an aged DHA-depleted APPsw AD mouse model. DHA also increased LR11 in a human neuronal line. In vivo elevation of LR11 was also observed with dietary fish oil in young rats with insulin resistance, a model for type II diabetes, another AD risk factor. These data argue that DHA induction of LR11 does not require DHA-depleting diets and is not age dependent. Because reduced LR11 is known to increase Abeta production and may be a significant genetic cause of LOAD, our results indicate that DHA increases in SorLA/LR11 levels may play an important role in preventing LOAD.
PMID: 18160637 [PubMed - indexed for MEDLINE]

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Altered Lipid Metabolism in Brain Injury and Disorders

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Adibhatla RM, Hatcher JF.
Subcell Biochem. 2008;48:nihpa41041.
Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A(2) IIA and lipoprotein-PLA(2) are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A(2) attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.

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The association study between DHCR24 polymorphisms and Alzheimer's disease

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Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144(7):906-10
The association study between DHCR24 polymorphisms and Alzheimer's disease
Lamsa R, Helisalmi S, Hiltunen M, Herukka SK, Tapiola T, Pirttila T, Vepsalainen S, Soininen H.
Unit of Neurology, Clinical Department, Brain Research Unit, Clinical Research Center, Mediteknia, University of Kuopio, 70211 Kuopio, Finland. riikka.lamsa@uku.fi

DHCR24 gene in chromosome 1 encodes seladin 1, a cholesterol synthesizing enzyme. Seladin 1 protects neurons from Abeta(42) mediated toxicity and participates in regulation of Abeta(42) formation by organizing the placement of APP cleaving beta-secretase in cholesterol-rich detergent-resistant membrane domains (DRMs). In Alzheimer's disease (AD) the level of seladin 1 in affected neurons is reduced, DRMs are disorganized and Abeta(42) formation is increased. To examine genetic association of the DHCR24 with AD, we genotyped four single nucleotide polymorphism (SNP) sites (rs638944, rs600491, rs718265, and rs7374) in 414 Finnish AD cases and 459 controls and calculated the allelic and genotypic distribution of both cases and controls. The single locus association analysis indicated that men carrying the T allele of rs600491 had an increased risk of AD (OR 1.7 95% CI 1.2-2.4; P = 0.004, Bonferroni corrected P = 0.048 with 12 tests). We estimated haplotypes of SNPs rs638944 and rs600491 between cases and controls and found overall distribution of haplotypes highly significant (P < 0.001). There was a common protective haplotype TC with frequency of 0.22 in cases and 0.30 in controls (P < 0.001) and a risk haplotype GC with frequency of 0.10 in cases and 0.05 in controls (P < 0.001). We also measured CSF Abeta(42), tau and phosphorylated tau (ptau) levels in a subgroup of AD cases (n = 44) and controls (n = 10) and found that AD cases that carry rs718265 GG had lower levels of Abeta(42) than other genotype carriers. Our findings indicate that DHCR24 gene may be associated with AD risk. (c) 2007 Wiley-Liss, Inc.

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An Apolipoprotein A-I Gene Promoter Polymorphism Associated with Cognitive Decline, but Not with Alzheimer's Disease

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Dement Geriatr Cogn Disord. 2007 Dec 10;25(2):97-102
Helbecque N, Codron V, Cottel D, Amouyel P.
INSERM, U744, Institut Pasteur de Lille, Universite de Lille 2, Lille, France.

Background/Aims: Accumulating biological and epidemiological evidence suggests a close link between cholesterol metabolism and the pathophysiology of Alzheimer's disease (AD). The observation that the use of statins reduces the risk of AD sustains this hypothesis. Apolipoprotein A-I (APOA1) is the major component of the high-density lipoproteins, particles involved in reverse cholesterol transport. Therefore, genetic polymorphisms in the gene encoding APOA1 might influence cholesterol metabolism and be a risk factor for AD. A previous study suggested an impact of a G-->A polymorphism at position -75 bp in the APOA1 gene on the risk for early-onset AD and on the age at onset of the disease. We studied this polymorphism in 3 independent European population samples. Methods: Genotyping was conducted asdescribed in the previous study. Results: We were unable to show any impact of this polymorphism on the risk of AD. Conversely, subjects bearing the A allele of this polymorphism were at risk of cognitive decline. Conclusion: Our resultssuggest an impact of the G-->A polymorphism at position -75 bp in the APOA1 gene on cognitive impairment, but not on the risk of AD. Copyright (c) 2007 S. Karger AG, Basel.

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Amyloid beta as a Regulator of Lipid Homeostasis

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Trends Mol Med. 2007 Aug;13(8):337-44. Epub 2007 Jul 17
Grimm MO, Grimm HS, Hartmann T.
Universitat des Saarlandes, Kirrberger Str. 61.4, D-66421 Homburg, Germany.

The beta-amyloid peptide (A beta) is widely considered to be the molecule that causes Alzheimer's disease (AD). Besides this pathological function of A beta, recently published data reveal that A beta also has an essential physiological role in lipid homeostasis. Cholesterol increases A beta production, and conversely A beta production causes a decrease in cholesterol synthesis. The latter appears to be mediated by the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), a key enzyme in cholesterol synthesis, in an action similar to that of statins. Moreover, A beta regulates sphingolipid metabolism by directly activating sphingomyelinases (SMases). This review summarizes the molecular basis for the known physiological functions of A beta and amyloid precursor protein (APP), the roles of A beta and APP in lipid homeostasis and the medical implications of addressing lipid homeostasis in respect to AD. This knowledge might provide new insights for current and future therapeutic approaches to AD.

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Levels of ApoE in cerebrospinal fluid are correlated with Tau and 24S-hydroxycholesterol in patients with cognitive disorders

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Neurosci Lett. 2007 Sep 25;425(2):78-82. Epub 2007 Aug 15.
Shafaati M, Solomon A, Kivipelto M, Bjorkhem I, Leoni V.
Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

Evidence was recently presented from in vitro studies that 24S-hydroxycholesterol acts as a signalling molecule inducing apoE-mediated cholesterol efflux from astrocytoma cells, and that there is a direct effect of the oxysterol on apoE transcription, protein synthesis and secretion. Consistent with this mechanism, a significant correlation is demonstrated here between levels of apoE and 24S-hydroxycholesterol in cerebrospinal fluid from patients with Alzheimer's disease and patients with mild cognitive impairment. Such a correlation was not found in control patients. There was no correlation between levels of apoE and cholesterol in cerebrospinal fluid from controls. The results are consistent with a close coupling between release of 24S-hydroxycholesterol and apoE secretion under conditions with neuronal degeneration. The levels of apoE in cerebrospinal fluid were also correlated to the levels of Tau and the possibility is discussed that the level of apoE in cerebrospinal fluid may be used as a marker of neurodegeneration.

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No association of genetic variants of liver X receptor-beta with Alzheimer's disease risk

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Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 14 [Epub ahead of print]
Rodriguez-Rodriguez E, Llorca J, Mateo I, Infante J, Sanchez-Quintana C, Garcia-Gorostiaga I, Fernandez-Viadero C, Pena N, Berciano J, Combarros O.
Neurology Service and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), "Marques de Valdecilla" University Hospital (University of Cantabria), Santander, Spain.

Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

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Cholesterol retention in Alzheimer's brain is responsible for high beta- and gamma-secretase activities and Abeta production

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Neurobiol Dis. 2007 Nov 4; [Epub ahead of print]
Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, Sue LI, Woulfe J, Xu H, Stanimirovic DB, Zhang W.
Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Canada K1A 0R6; Faculty of Medicine, University of Ottawa, Ottawa, Canada.

Alzheimer's disease (AD) is characterized by overproduction of Abeta derived from APP cleavage via beta- and gamma-secretase pathway. Recent evidence has linked altered cholesterol metabolism to AD pathogenesis. In this study, we show that AD brain had significant cholesterol retention and high beta- and gamma-secretase activities as compared to age-matched non-demented controls (ND). Over one-half of AD patients had an apoE4 allele but none of the ND. beta- and gamma-secretase activities were significantly stimulated in vitro by 40 and 80 muM cholesterol in AD and ND brains, respectively. Both secretase activities in AD brain were more sensitive to cholesterol (40 muM) than those of ND (80 muM). Filipin-stained cholesterol overlapped with BACE and Abeta in AD brain sections. Cholesterol (10-80 muM) added to N2a cultures significantly increased cellular cholesterol, beta- and gamma-secretase activities and Abeta secretion. Similarly, addition of cholesterol (20-80 muM) to cell lysates stimulated both in vitro secretase activities. Ergosterol slightly decreased beta-secretase activity at 20-80 muM, but strongly inhibited gamma-secretase activity at 40 muM. Cholesterol depletion reduced cellular cholesterol, beta-secretase activity and Abeta secretion. Transcription factor profiling shows that several key nuclear receptors involving cholesterol metabolism were significantly altered in AD brain, including decreased LXR-beta, PPAR and TR, and increased RXR. Treatment of N2a cells with LXR, RXR or PPAR agonists strongly stimulated cellular cholesterol efflux to HDL and reduced cellular cholesterol and beta-/gamma-secretase activities. This study provides direct evidence that cholesterol homeostasis is impaired in AD brain and suggests that altered levels or activities of nuclear receptors may contribute to cholesterol retention which likely enhances beta- and gamma-secretase activities and Abeta production in human brain.

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LDL receptor deficiency results in decreased cell proliferation and presynaptic

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Neurosci Res. 2007 Nov;59(3):251-6. Epub 2007 Jul 17.
Mulder M, Koopmans G, Wassink G, Al Mansouri G, Simard ML, Havekes LM,
Prickaerts J, Blokland A.
Department of Molecular Cell Biology, University of Maastricht, Maastricht, The
Netherlands.


An aberrant cholesterol metabolism in the brain may contribute to the
pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) regulates
plasma cholesterol levels and recently we and others obtained evidence that it
is also involved in regulating brain cholesterol homeostasis. Moreover, we found
that LDLR-deficient mice display impaired spatial memory. Because cholesterol,
in part derived from cellular uptake via LDLR, is required for peripheral cell
proliferation and growth, we examined the effect of absence of the LDLR on
hippocampal proliferation and the density of synaptic connections. Mice
deficient for the LDLR displayed a reduced number of proliferating
(BrdU-labeled) cells in the hippocampus as compared to wild type control mice.
In addition, the number of synaptophysin-immunoreactive presynaptic boutons in
the hippocampal CA1 and the dentate gyrus (DG) areas, but not in cortical areas,
was lower in the LDLR-knockout mice than in the control mice. In vitro
experiments showed that LDLR activity is increased when cell growth is enhanced
by the addition of N2 supplement. This further supports a role for the LDLR in
the outgrowth of neurites. These findings support the notion that, similar to
its role in the periphery, the LDLR is important for the cellular uptake of
cholesterol in the brain and that disturbance of this process affects neuronal
plasticity.

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Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol and calcium homeostasis prior to synaptic dysfunction

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Neurobiol Dis. 2007 Oct;28(1):52-64. Epub 2007 Jun 23
Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction
Ahtiainen L, Kolikova J, Mutka AL, Luiro K, Gentile M, Ikonen E, Khiroug L, Jalanko A, Kopra O.
National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, PO Box 104, 00251 Helsinki, Finland.

Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of children, characterized by selective death of neocortical neurons. To understand early disease mechanisms in INCL, we have studied Ppt1(Deltaex4) knock-out mouse neurons in culture and acute brain slices. Global transcript profiling showed deregulation of key neuronal functions in knock-out mice including cholesterol metabolism, neuronal maturation, and calcium homeostasis. Cholesterol metabolism showed major changes; sterol biosynthesis was enhanced and steady-state amounts of sterols were altered at the cellular level. Changes were also present in early maturation of Ppt1(Deltaex4) neurons indicated by increased proliferative capacity of neuronal stem cells. Knock-out neurons presented unaltered electrophysiological properties suggesting uncompromised synaptic function in young animals. However, knock-out neurons exhibited more efficient recovery from glutamate-induced calcium transients, possibly indicating neuroprotective activation. This study established that the neuronal deregulation in INCL is linked to neuronal maturation, lipid metabolism and calcium homeostasis.

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Squalestatin protects neurons and reduces the activation of cytoplasmic phospholipase A2 by Abeta(1-42)

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Neuropharmacology. 2007 Aug;53(2):222-31. Epub 2007 May 18
Bate C, Williams A.
Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL9 7TA, UK

Alzheimer's disease is characterised by the loss of neurons and the production of Abeta peptides. We report that the addition of Abeta(1-42) to neurons resulted in activation of cytoplasmic phospholipase A(2) (cPLA(2)), the production of prostaglandin E(2), synapse damage and reduced neuronal survival. Pre-treatment with simvastatin, a clinically relevant statin that penetrates the brain, protected against Abeta(1-42) induced synapse damage and neuronal death in vitro. The neuroprotective effects of simvastatin were shared by squalestatin, a squalene synthase inhibitor that reduces neuronal cholesterol production and crucially, does not affect isoprenoid formation. The protective effect of both these drugs was reversed by the addition of exogenous cholesterol. These drugs did not alter the amounts of extracellular Abeta(1-42) ingested by neurons; rather they reduced Abeta(1-42) induced activation of cPLA(2) and prostaglandin E(2) production. Treatment prevented the migration of Abeta(1-42) and cPLA(2) to caveolin-1 containing lipid rafts. We propose that critical concentrations of Abeta(1-42) trigger the amalgamation of individual micro-domains containing signalling molecules to form lipid raft platforms in which sustained activation of cPLA(2) leads to neuronal dysfunction and ultimately neuronal death. This process is dependent on the amounts of cholesterol in neuronal membranes and is susceptible to treatment with squalestatin or simvastatin.

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A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer's disease

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Neurobiol Aging. 2007 Dec;28(12):1834-9. Epub 2006 Sep 25
Selley ML.
Angiogen Pharmaceuticals Pty. Ltd., Level 31, ABN AMRO Tower, 88 Phillip Street, Sydney, NSW 2000, Australia

There is evidence that vascular risk factors contribute to the pathology of Alzheimer's disease. Increased concentrations of circulating homocysteine are associated with vascular risk factors and Alzheimer's disease but the mechanisms involved are unclear. Homocysteine inhibits the hydrolysis of S-adenosylhomocysteine (SAH) which is a product inhibitor of S-adenosylmethionine (SAM) dependent methyltransferase reactions. It has been shown previously that SAH inhibits phosphatidylethanolamine N-methyltransferase (PEMT) in the liver. The activity of PEMT in the liver plays an important role in the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) and the delivery of essential polyunsaturated fatty acids (PUFAs) to peripheral tissues. In the present study, the plasma concentrations of SAH, SAM and homocysteine and the erythrocyte composition of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and their respective polyunsaturated fatty acid concentrations were determined in 26 patients with Alzheimer's disease and compared to those in 29 healthy control subjects. There was a significant increase in the plasma concentrations of SAH (p<0.001) and homocysteine (p<0.001) and a significant increase in the plasma concentrations of SAM (p<0.001) in the Alzheimer's patients. A significant positive correlation was found between the plasma concentrations of SAH and homocysteine (r=0.738, p<0.001). There was a negative correlation between the plasma concentrations of homocysteine and the ratio of SAM/SAH (r=-0.637, p<0.01). There was a significant decrease in the erythrocyte content of PC (p<0.001) and an increase in the erythrocyte content of PE (p<0.001) in the Alzheimer's patients. Plasma SAH concentrations were negatively related to erythrocyte PC concentrations (r=-0.286, p<0.01) and positively related to erythrocyte PE concentrations (r=0.429, p<0.001). The erythrocyte PC from Alzheimer's patients had a significant depletion of docosahexaenoic acid (DHA) (p<0.001) while there was no significant difference in the DHA content of erythrocyte PE. There was a significant negative correlation between plasma SAH and the DHA composition of erythrocyte PC (r=-0.271, p<0.001). This data may reflect the inhibition of hepatic PEMT activity by SAH in Alzheimer's disease. The decreased mobilization of DHA from the liver into plasma and peripheral tissues may increases the risk of atherosclerosis and stroke leading to chronic cerebral hypoperfusion. The evidence suggests that a metabolic link between the increased production of SAH and phospholipid metabolism may contribute to cerebrovascular and neurodegenerative changes in Alzheimer's disease.

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Native and oxidized low-density lipoproteins modulate the vasoactive actions of soluble beta-amyloid peptides in rat aorta

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Clin Sci (Lond) 2007 Dec;113(11):427-34
Smith CC, Stanyer L, Betteridge DJ, Cooper MB.
The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, UK

Cerebrovascular accumulation of Abeta (beta-amyloid) occurs in aging and AD (Alzheimer's disease). Hypercholesterolaemia, which is associated with raised plasma LDL (low-density lipoprotein), may predispose to AD. Soluble Abeta is found in the circulation and enhances vasoconstriction. Under conditions that may favour the formation of short Abeta oligomers, as opposed to more severe polymerization leading to Abeta fibrillogenesis, we investigated the influence of LDLs on the vasoactive actions of soluble Abeta. Thus the actions of Abeta40 and Abeta42 in combination with native or oxidized LDL on vasoconstriction to NA (noradrenaline) and vasodilatation to ACh (acetylcholine) were examined in rat aortic rings. LDL, particularly when oxidized, potentiated NA-induced constriction when combined with soluble Abeta40 and, especially, Abeta42. Soluble Abeta40 reduced relaxation induced by ACh, but Abeta42 was ineffective. Native and oxidized LDL also attenuated relaxation. Synergism occurred between oxidized LDL and Abeta with respect to ACh-induced relaxation, but not between native LDL and Abeta. We have shown for the first time that, under conditions that may result in Abeta oligomer formation, LDL, particularly when oxidized, modulates the vascular actions of soluble Abeta to extents greater than those reported previously for fibrillar Abeta preparations. Mechanisms whereby a treatable condition, namely hypercholesterolaemia, might contribute to the development of the cerebrovascular component of AD are indicated.

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Dietary patterns and risk of dementia: the Three-City cohort study

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Neurology. 2007 Nov 13;69(20):1921-30
Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alperovitch A.
INSERM, U593, University Victor Segalen Bordeaux 2, case 11, 146 rue Leo-Saignat, F-33076 Bordeaux cedex, France.

BACKGROUND: Dietary fatty acids and antioxidants may contribute to decrease dementia risk, but epidemiologic data remain controversial. The aim of our study was to analyze the relationship between dietary patterns and risk of dementia or Alzheimer disease (AD), adjusting for sociodemographic and vascular risk factors, and taking into account the ApoE genotype. METHODS: A total of 8,085 nondemented participants aged 65 and over were included in the Three-City cohort study in Bordeaux, Dijon, and Montpellier (France) in 1999-2000 and had at least one re-examination over 4 years (rate of follow-up 89.1%). An independent committee of neurologists validated 281 incident cases of dementia (including 183 AD). RESULTS: Daily consumption of fruits and vegetables was associated with a decreased risk of all cause dementia (hazard ratio [HR] 0.72, 95% CI 0.53 to 0.97) in fully adjusted models. Weekly consumption of fish was associated with a reduced risk of AD (HR 0.65, 95% CI 0.43 to 0.994) and all cause dementia but only among ApoE epsilon 4 noncarriers (HR 0.60, 95% CI 0.40 to 0.90). Regular use of omega-3 rich oils was associated with a decreased risk of borderline significance for all cause dementia (HR 0.46, 95% CI 0.19 to 1.11). Regular consumption of omega-6 rich oils not compensated by consumption of omega-3 rich oils or fish was associated with an increased risk of dementia (HR 2.12, 95% CI 1.30 to 3.46) among ApoE epsilon 4 noncarriers. CONCLUSION: Frequent consumption of fruits and vegetables, fish, and omega-3 rich oils may decrease the risk of dementia and Alzheimer disease, especially among ApoE epsilon 4 noncarriers.

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