NOTEWORTHY ARTICLES 2007 (January-June)

NoL Noteworthy New Format (started July 1, 2007)

Neurobiology of Lipids 'Noteworthy' section alerts interested readers about the selected noteworthy original research (not review) articles and meeting reports (published in other journals) on the subject of the Neurobiology of Lipids scope.

The reference to each article may be accompanied by the referee name (a member of the Neurobiology of Lipids editorial board or a journal reader), the authors' key note comments, the date of the 'noteworthy' alert, NoL letter to editor, and links to related articles (if any).

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Reversal of memory deficits by Atorvastatin and Simvastatin in rats
Parle M, Singh N.
Pharmacology Division, Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, India
Yakugaku Zasshi. (July 2007) 127(7): 1125-1137.
[PubMed] [Authors contact]
 

Article Abstract: "The present study was undertaken to investigate the beneficial effects of Atorvastatin and Simvastatin in cognitive dysfunctions of rats. Alprazolam, Scopolamine and high fat diet (HFD) induced amnesia served as interoceptive memory models where as, Water-maze and Elevated plus-maze served as exteroceptive models. A total of 38 groups of rats were used in this investigation. Escape latency time (ELT) recorded during acquisition trials conducted from day 1 to day 4, in water maze was taken as an index of acquisition, where as mean time spent in target quadrant during retrieval trial on day 5, was taken as the index of retrieval (memory). On elevated plus-maze, transfer latency (TL) measured on 1st d served as the index of acquisition and TL recorded on 2nd d was taken as the index of retrieval (memory). Alprazolam (0.5 mg kg(-1) intraperitoneally), Scopolamine (0.4 mg kg(-1) intraperitoneally) and HFD treated (for 90 days) rats exhibited amnesia as reflected by impairment in learning ability as well as memory, when tested on both, water maze and elevated plus maze. Atorvastatin (5 mg kg(-1) orally) as well as Simvastatin (5 mg kg(-1) orally) significantly attenuated Alprazolam, Scopolamine and HFD induced amnesia. These results highlight the ameliorative role of statins in experimental amnesia with possible involvement of their cholesterol dependent as well as cholesterol independent actions."

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ApoE allelic variability influences pupil response to cholinergic challenge and cognitive impairment
Scinto LF.
Laboratory of Higher Cortical Functions, Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
Genes Brain Behav. (April 2007) 6(3): 209-315. ePub 8 June 2006
[PubMed] [Authors contact]
 

Article Abstract: "Exaggerated pupil response to dilute tropicamide has been suggested as an early biological marker for Alzheimer's disease. The current study links apolipoprotein E (ApoE) allelic variability to the magnitude of pupil response in a sample of community-dwelling elderly without a diagnosis of Alzheimer's disease or dementia. Possession of an epsilon 4 allele influences both the likelihood of exhibiting an exaggerated pupil response above a predetermined cut-off (13% above baseline diameter) and the absolute overall magnitude of the response. Allelic variability was also shown to correlate with cognitive impairments in memory and attention. The data in this study further elucidate the nature of the biological bond between an exaggerated pupil response and the pathology of Alzheimer's disease. ApoE allelic variability is probably linked to pupil response through its influence on tau hyperphosphorylation. The early Alzheimer's pathology seen in the Edinger-Westphal area of cranial nerve III, a major centre for pupil control, is primarily tau-based with significant cell loss in this nucleus leading to central denervation hypersensitivity even in elderly who are clinically silent but who have early pathology."

selected by Alexei Koudinov | This item permanent URL

Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition
Wang D, Burhans LB, Gonzales-Joekes J, Deci S, Stankovic G, Sparks DL.
Blanchette Rockefeller Neurosciences Institute and Department of Physiology and Pharmacology, West Virginia University, P.O. Box 9302, Morgantown, WV, USA.
Behav Brain Res. (22 July 2007) 181(1): 52-63. Epub 30 March 2007
[PubMed] [Authors contact]
 

Article Abstract: "The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory."

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LDL receptor deficiency results in decreased cell proliferation and presynaptic bouton density in the murine hippocampus
Mulder M, Koopmans G, Wassink G, Mansouri GA, Simard ML, Havekes LM, Prickaerts J, Blokland A
Department of Molecular Cell Biology, University of Maastricht, Maastricht, The Netherlands
Neurosci Res. (ePub 17 July 2007)
[PubMed] [Related article 1 | 2 | 3] [Authors contact]
 

Article Abstract: "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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Effects of ApoE genotype and mild cognitive impairment on implicit learning
Negash S, Petersen LE, Geda YE, Knopman DS, Boeve BF, Smith GE, Ivnik RJ, Howard DV, Howard JH Jr, Petersen RC.
Mayo Clinic, Rochester, MN 55905, USA.
Neurobiol Aging. (June 2007) 28(6): 885-893 EPub 15 May 2006
[PubMed] [Authors contact]
 

Article Abstract: "The goals were to investigate implicit learning in mild cognitive impairment (MCI), and to determine the relations of implicit learning systems to apolipoprotein E (ApoE) genotype in healthy controls. Elderly controls grouped by ApoE status (ApoE-e4 allele carriers versus ApoE-e4 allele non-carriers) and MCI patients participated in the study. Individuals in all three groups completed both contextual cueing and serial reaction time (SRT) tasks. In the former, people learn to use repeated spatial configurations to facilitate search for a target, whereas in the latter, they learn to use subtle sequence regularities to respond more quickly and accurately to a series of events. Results revealed that healthy elderly individuals carrying the ApoE-e4 allele showed contextual cueing deficits compared to those who did not carry the ApoE-e4 allele. Further, elderly controls carrying the ApoE-e4 allele revealed similar amounts of contextual cueing as the MCI group, while the non-carriers performed better. Sequence learning, by contrast, was uninfluenced by either MCI or by ApoE genotype in healthy controls. This study provides further support for the medial temporal lobe dysfunction and relative integrity of fronto-striatal systems in MCI, and indicates the influence of ApoE genotype on implicit learning even in healthy older individuals without cognitive impairment."

selected by Alexei Koudinov | This item permanent URL

Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease
Sundar PD, Feingold E, Minster RL, DeKosky ST, Kamboh MI.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Neurobiol Aging. (June 2007) 28(6): 856-862 ePub 24 May 2006
[PubMed] [Authors contact]
 

Article Abstract: "Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by a complex interaction of genetic and environmental factors. Increasing evidence highlights a potential role for cholesterol in the pathophysiology of AD. The ABCA1 gene, located in close vicinity to the 9q linkage peaks identified by genome-wide AD linkage studies, plays an important role in cellular cholesterol efflux, and is likely a good candidate gene. However, results from published genetic association studies between ABCA1 and AD are ambiguous. In the present study, we examined the role of two ABCA1 polymorphisms, R219K (rs2230806) and G-17C (rs2740483) in modifying the risk of late-onset AD (LOAD) in a large American white cohort of 992 AD cases and 699 controls. We observed significant gender x R219K interaction (p=0.00008). Female carriers of the 219K allele showed a 1.75-fold increased risk of developing AD compared to non-219K carrier females (95% CI 1.34-2.29; p=0.00004). The overall two-site haplotype distribution was also significant between female AD cases and controls (p=0.017). The risk associated with the R219K polymorphism was independent of the recently reported significant association in the ubiquilin (UBQLN1) gene in this region on chromosome 9q. Our data suggest a gender-specific and APOE and UBQLN1 independent association between the ABCA1/R219K polymorphism and LOAD."

selected by Alexei Koudinov | This item permanent URL

Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease
Sundar PD, Feingold E, Minster RL, DeKosky ST, Kamboh MI.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Neurobiol Aging. (June 2007) 28(6): 856-862 ePub 24 May 2006
[PubMed] [Authors contact]
 

Article Abstract: "Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by a complex interaction of genetic and environmental factors. Increasing evidence highlights a potential role for cholesterol in the pathophysiology of AD. The ABCA1 gene, located in close vicinity to the 9q linkage peaks identified by genome-wide AD linkage studies, plays an important role in cellular cholesterol efflux, and is likely a good candidate gene. However, results from published genetic association studies between ABCA1 and AD are ambiguous. In the present study, we examined the role of two ABCA1 polymorphisms, R219K (rs2230806) and G-17C (rs2740483) in modifying the risk of late-onset AD (LOAD) in a large American white cohort of 992 AD cases and 699 controls. We observed significant gender x R219K interaction (p=0.00008). Female carriers of the 219K allele showed a 1.75-fold increased risk of developing AD compared to non-219K carrier females (95% CI 1.34-2.29; p=0.00004). The overall two-site haplotype distribution was also significant between female AD cases and controls (p=0.017). The risk associated with the R219K polymorphism was independent of the recently reported significant association in the ubiquilin (UBQLN1) gene in this region on chromosome 9q. Our data suggest a gender-specific and APOE and UBQLN1 independent association between the ABCA1/R219K polymorphism and LOAD."

selected by Alexei Koudinov | This item permanent URL

The cholesteryl ester transfer protein (CETP) gene and the risk of Alzheimer's disease
Arias-Vasquez A, Isaacs A, Aulchenko YS, Hofman A, Oostra BA, Breteler M, van Duijn CM.
Department of Epidemiology & Biostatistics, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
Neurogenetics. (ePub 15 May 2007)
[PubMed] [Authors contact]
 

Article Abstract: "Like the apolipoprotein E (APOE) gene, the most common genetic determinant for Alzheimer's disease (AD), the cholesteryl ester transfer protein ( CETP) is involved in lipid metabolism. We studied the I405V polymorphism of the CETP gene in relation to AD. We genotyped 544 AD cases and 5,404 controls from the Rotterdam study, using a TaqMan allelic discrimination assay. Odds ratios (ORs) for AD were estimated using logistic regression analysis. CETP VV carriers showed significantly increased high-density lipoprotein levels compared to the IV and II carriers. In the overall analysis of AD, the risk of disease for the VV carriers of the CETP polymorphism was non-significantly increased compared to II carriers OR(VV) = 1.33, 95% confidence interval (CI) 0.96-1.90 p = 0.08). In those without the APOE*4 allele, the risk of AD for VV carriers was increased 1.67-fold (95% CI 1.11-2.52, p = 0.01). The difference in the relationship between CETP and AD between APOE*4 carriers and APOE*4 non-carriers was statistically significant (p for interaction = 0.04). Our results suggest that the VV genotype of the I405V polymorphism of the CETP gene increases the risk of AD in the absence of the APOE*4 allele, probably through a cholesterol metabolism pathway in the brain."

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Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer's disease
Hirsch-Reinshagen V, Wellington CL.
Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Curr Opin Lipidol. (June 2007) 18(3): 325-332
[PubMed] [Related article 1| 2] [Authors contact]
 

Article Abstract: "PURPOSE OF REVIEW: Recent evidence suggests that cholesterol metabolism participates in the pathogenesis of Alzheimer's disease. Apolipoprotein E is the main lipid carrier in the brain and the best-established risk factor for late-onset Alzheimer's disease. Intracellular cholesterol levels influence the generation of amyloid-beta peptides, the toxic species thought to be a primary cause of Alzheimer's disease. Finally, compounds that modulate cholesterol metabolism affect amyloid-beta generation. This review summarizes data linking apolipoprotein E and adenosine triphosphate-binding cassette transporters to aspects of cholesterol metabolism and Alzheimer's disease pathogenesis. RECENT FINDINGS: In vivo, the lipidation status of apolipoprotein E affects amyloid-beta burden in mice with Alzheimer's disease, which appears to caused by the modulation of amyloid-beta deposition or clearance rather than amyloid-beta production. State-of-the-art in-vivo assays reveal that amyloid-beta is cleared from the brain by multiple pathways. Members of the adenosine triphosphate-binding cassette superfamily of transporters regulate lipid homeostasis and apolipoprotein metabolism in the brain, and may affect Alzheimer's disease pathogenesis by modulating apolipoprotein E lipidation as well as intracellular sterol homeostasis. SUMMARY: Proteins involved in brain cholesterol metabolism may affect the pathogenesis of Alzheimer's disease. Compounds that modulate the expression of these proteins may be of therapeutic benefit in Alzheimer's disease."

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Caveolin-1 and -2 and their relationship to cerebral amyloid angiopathy in Alzheimer's disease
van Helmond ZK, Miners JS, Bednall E, Chalmers KA, Zhang Y, Wilcock GK, Love S, Kehoe PG
Dementia Research Group, Institute of Clinical Neurosciences, Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol, UK
Neuropathol Appl Neurobiol. (June 2007) 33(3): 317-327
[PubMed] [Authors contact]
 

Article Abstract: "Cerebral amyloid angiopathy (CAA) affects over 90% of patients with Alzheimer's disease (AD) and increases the risk of cerebral haemorrhage and infarction. Caveolae - cholesterol-enriched plasmalemmal microinvaginations - are implicated in the production of amyloid beta peptide (Abeta). Caveolin-1 (CAV-1) is essential for the formation of caveolae. Caveolin-2 (CAV-2) is expressed at the plasma membrane only when in a stable hetero-oligomeric complex with CAV-1. CAV-1 and CAV-2 are highly co-expressed by endothelium and smooth muscle. Recent studies suggest that down-regulation of CAV-1 causes a reduction in alpha-secretase activity and consequent accumulation of Abeta. We have used quantitative immunohistochemical techniques to assess the relationship between CAV-1 and CAV-2 with respect to Abeta accumulation in the cerebral vasculature in a series of post mortem brains. CAV-1 and CAV-2 were co-expressed within the tunica media and endothelium of cerebral blood vessels. There were regional differences in CAV-1 immunolabelling, which was significantly greater in the frontal cortex and white matter than in the parietal lobe (in both control and AD cases) or the temporal lobe (in AD alone). However, CAV-1 labelling in AD did not differ from that in controls in any of the three lobes examined. Assessment of CAV-1 labelling in relation to the severity of CAA showed CAV-1 to be significantly increased in the frontal white matter in a subgroup of AD cases with absent/mild CAA compared with controls with absent/mild CAA and to AD cases with moderate/severe CAA, but the latter groups did not show significant differences from one another. CAV-1 labelling did not vary with age, gender, APOE genotype, post mortem delay or brain weight. Only segments of blood vessels with particularly abundant Abeta and extensive loss of smooth muscle actin showed loss of CAV-1 and CAV-2 from the tunica media. Within these vessels endothelial CAV-1 was preserved and discontinuous CAV-2 labelling was noted along the outer aspect of the vessel wall. Our findings suggest that alterations in the expression of vascular CAV-1 and CAV-2 are unlikely to play a role in the development of CAA in AD."

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Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease?
Katsel P, Li C, Haroutunian V.
Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6575, USA
Neurochem Res. (April-May 2007) 32(4-5): 845-856. ePub 7 March 2007
[PubMed] [Authors contact]
 

Article Abstract: "There is mounting evidence linking Abeta42 generation in Alzheimer's disease (AD) with sphingomyelin catabolism. Using microarray technology to study 17 brain regions from subjects with varying severity of AD and dementia we detected multiple gene expression abnormalities of the key enzymes that control sphingolipid metabolism. These changes were correlated with the progression of clinical dementia. The upregulation of gene expression of the enzymes controlling synthesis de novo of Cer and the downregulation of the enzymes involved in glycosphingolipid synthesis was evident as early in disease progression as in mild dementia. Together these changes suggest a shift in sphingolipid metabolism towards accumulation of Cer, depletion of glycosphingolipids and the reduction of synthesis of the anti-apoptosis signaling lipid-sphingosine 1-phosphate as a function of disease progression. This disrupted balance within the sphingolipid metabolism may trigger signaling events promoting neurodegeneration across cortical regions. This potential mechanism may provide a link between lipid metabolism disturbance and AD."

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Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer's disease
Chin J, Massaro CM, Palop JJ, Thwin MT, Yu GQ, Bien-Ly N, Bender A, Mucke L.
Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, California 94158, USA
J Neurosci. (14 March 2007) 27(11): 2727-2733
[PubMed] [Authors contact]
 

Article Abstract: "Reelin regulates nervous system development and modulates synaptic plasticity in the adult brain. Several findings suggest that alterations in Reelin signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD). Cell surface receptors for Reelin, including integrins and very-low-density lipoprotein receptor/apolipoprotein E2 receptor, may be targets of amyloid-beta (Abeta) peptides presumed to play key roles in the pathogenesis of AD. Reelin also regulates the extent of tau phosphorylation. Finally, increased amounts of Reelin fragments have been found in CSF from AD patients, suggesting altered processing of Reelin. We therefore hypothesized that Reelin levels might be altered in the brains of human amyloid precursor protein (hAPP) transgenic mice, particularly in brain regions vulnerable to AD such as hippocampus and entorhinal cortex. Compared with nontransgenic controls, hAPP mice had significantly fewer Reelin-expressing pyramidal cells in the entorhinal cortex, the major population of glutamatergic neurons expressing Reelin in the brain. Western blot analysis of the hippocampus, which receives projections from the entorhinal cortex, revealed significant reductions in Reelin levels. In contrast, the number of Reelin-expressing GABAergic interneurons was not altered in either the entorhinal cortex or the hippocampus. Thus, neuronal expression of hAPP/Abeta is sufficient to reduce Reelin expression in a specific population of entorhinal cortical pyramidal neurons in vivo. Underscoring the relevance of these findings, we found qualitatively similar reductions of Reelin-expressing pyramidal neurons in the entorhinal cortex of AD brains. We conclude that alterations in Reelin processing or signaling may be involved in AD-related neuronal dysfunction."

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Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain
Dyall SC, Michael GJ, Whelpton R, Scott AG, Michael-Titus AT.
Neuroscience Centre, Institute of Cell and Molecular Sciences, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, Whitechapel, London, United Kingdom.
Neurobiol Aging (Mar 2007) 28(3): 424-39. ePpub 28 Feb 2007
[PubMed] [Authors contact]
 

Article Abstract: "Ageing is associated with a decrease in the brain content of omega-3 polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and with decreased neuroplasticity. The glutamate receptor subunits GluR2 and NR2B play a significant role in forebrain synaptic plasticity. We investigated GluR2 and NR2B in the aged prefrontal cortex, hippocampus and striatum, and tested if treatment with a preparation containing EPA and DHA can reverse age-related changes. The study compared adult and old (3-4 and 24-26 month) rats, and the latter were fed a standard diet or a diet supplemented for 12 weeks with omega-3 PUFA at 270mg/kg/day (ratio EPA to DHA 1.5:1). Ageing was associated with decreases in the GluR2 and NR2B subunits in all structures. These decreases were fully reversed by omega-3 PUFA supplementation. Age-related changes in the phospholipid PUFA content were also seen. Decreases in DHA were mostly corrected by supplementation. This study supports the neuroprotective effect of omega-3 fatty acids in brain ageing, and illustrates specific mechanisms underlying this effect."

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Measures of adiposity and dementia risk in elderly persons
Luchsinger JA, Patel B, Tang MX, Schupf N, Mayeux R
Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Departments of Epidemiology and Biostatistics, Joseph P. Mailman School of Public Health, and Gertrude H. Sergievsky Center, Columbia University
Arch Neurol (March 2007) 64(3): 392-398
[PubMed] [Authors contact]
 

Abstract: "Studies relating adiposity to dementia are conflicting. We explored the associations of body mass index (BMI), (calculated as weight in kilograms divided by the square of height in meters) waist circumference, and weight change to dementia, probable Alzheimer disease, and dementia associated with stroke (DAS). DESIGN: Persons without dementia were followed up for 5 years; 893 persons had BMI data, 907 had waist circumference data, and 709 had a second weight measurement. Dementia was ascertained using standard methods. Cox proportional hazards regression was used for analyses using follow-up as time to event, adjusting for demographics and apolipoprotein E-epsilon4 status. RESULTS: Compared with persons in the first quartile of BMI, persons in the third quartile had a lower dementia and Alzheimer disease risk and persons in the second quartile had a lower DAS risk. The association between BMI and dementia resembled a U shape in those younger than 76 years, while dementia risk decreased with higher BMI in those 76 years and older. The fourth quartile of waist circumference was related to a higher DAS risk in the whole sample, and to dementia and Alzheimer disease in persons younger than 76 years. Weight loss was related to a higher dementia and DAS risk, and weight gain was related to a higher DAS risk only. CONCLUSIONS: The prospective association between adiposity and dementia differs depending on the anthropometric measure used, and is modified by age. This may explain previous conflicting reports."

selected by Ilya Reznik | This item permanent URL

Memory enhancing activity of Anwala churna (Emblica officinalis Gaertn.): An Ayurvedic preparation
Vasudevan M, Parle M.
Pharmacology Division, Department of Pharmaceutical Sciences, Post Box - 38, Guru Jambheshwar University of Science and Technology, Hisar, (Haryana) -125 001, India.
Physiol Behav (8 Feb 2007) (Epub ahead of print)
[PubMed] [Authors contact]
 

Abstract: "Ayurveda means "the science of life". Ayur means "life" and Veda means "knowledge or science". It is the oldest medical system in the world. Its origins can be traced as far back as 4500 BC, to four ancient books of knowledge, (the "Vedas") and it is still officially recognized by the government of India. The present study was aimed at investigating the effects of Anwala churna (Emblica officinalis Gaertn.), an Ayurvedic preparation on memory, total serum cholesterol levels and brain cholinesterase activity in mice. Anwala churna was administered orally in three doses (50, 100 and 200 mg/kg) for fifteen days to different groups of young and aged mice. Elevated plus maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam-, scopolamine- and ageing-induced amnesia served as the interoceptive behavioral models. Total serum cholesterol levels and brain cholinesterase activity also estimated. Anwala churna (50, 100 and 200 mg/kg, p.o.) produced a dose-dependent improvement in memory scores of young and aged mice. Furthermore, it reversed the amnesia induced by scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.). Interestingly, brain cholinesterase activity and total cholesterol levels were reduced by Anwala churna administered orally for 15 days. Anwala churna may prove to be a useful remedy for the management of Alzheimer's disease on account of its multifarious beneficial effects such as, memory improving property, cholesterol lowering property and anticholinesterase activity"

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Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1
Hayashi H, Campenot RB, Vance DE, Vance JE.
Group on Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
J Neurosci. (21 Feb 2007) 27(8): 1933-1941
[PubMed] [Authors contact]
 

Abstract: "Apolipoprotein E (apoE)-containing lipoproteins (LPs) are secreted by glia and play important roles in lipid homeostasis in the CNS. Glia-derived LPs also promote synaptogenesis and stimulate axon growth of CNS neurons. Here, we provide evidence that glia-derived LPs protect CNS neurons from apoptosis by a receptor-mediated signaling pathway. The protective effect was greater for apolipoprotein E3 than for apolipoprotein E4, the expression of which is a risk factor for Alzheimer's disease. The anti-apoptotic effect of LPs required the association of apolipoprotein E with lipids but did not require cholesterol. Apoptosis was not prevented by lipids alone or by apoA1- or apoJ-containing lipoproteins. The prevention of neuronal apoptosis was initiated after the binding of LPs to the low-density lipoprotein receptor-related protein (LRP), a multifunctional receptor of the low-density lipoprotein receptor family. We showed that inhibition of LRP activation, by treatment of neurons with receptor-associated protein or anti-LRP antibodies, or by LRP gene-silencing experiments, reduced the protective effect of LPs. Furthermore, another LRP ligand, alpha2-macroglobulin, also protected the neurons from apoptosis. After binding to LRP, LPs initiate a signaling pathway that involves activation of protein kinase Cdelta and inactivation of glycogen synthase kinase-3beta. These findings indicate the potential for using glial lipoproteins or an activator of the LRP signaling pathway for treatment for neurodegenerative disorders such as Alzheimer's disease."

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Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness
Reiman EM, Alexander GE, Sibley BA, Tessier D, McLemore EC.
Department of Exercise and Sport Science, University of North Carolina, Greensboro, NC 27402, USA.
Med Sci Sports Exerc. (Jan 2007) 39(1): 199-207
[PubMed] [Authors contact]
 

Abstract: "INTRODUCTION: Apolipoprotein E (ApoE) genotype and aerobic fitness are each associated with cognitive performance in older adults. However, their potentially interactive effects on cognitive performance have not been examined. PURPOSE: The primary purpose of this study was to determine whether ApoE genotype and aerobic fitness interact to uniquely impact memory performance and executive functioning. A secondary purpose was to examine the interactive effects on other measures of cognition to provide a more comprehensive assessment of cognitive abilities across a broad range of functions. METHODS: Community-dwelling, cognitively normal older women (N = 90) provided blood samples to allow for assessment of ApoE genotype, completed cognitive tests, and performed a maximal aerobic fitness test. Primary outcome variables were the auditory verbal learning test (AVLT), the complex figures test (CFT), and the Wisconsin card-sorting task (WCST). Secondary outcome variables were the block design test and the paced auditory serial addition task (PASAT). RESULTS: Regression analyses indicated that aerobic fitness was associated with significantly better performance on measures of the AVLT, the CFT, and the PASAT for the ApoE-epsilon4 homozygotes. CONCLUSION: The preliminary findings from this study support the possibility that aerobic fitness is positively associated with the memory performance of those individuals at most genetic risk for Alzheimer disease."

selected by Alexei Koudinov | This item permanent URL

selected by Alexei Koudinov | This item permanent URL

APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD)
Watts GD, Adamson JL, Hutton M, Umberger G, Xiong S, Ramdeen S, Lovell MA, Kimonis VE, Smith CD.
Children's Hospital Clinical Genetics and Metabolism, Boston, Massachusetts, and Department of Neurology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
Genet Med. (Jan 2007) 9(1): 9-13
[PubMed] [Authors contact]
 

Abstract: " Inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia is an adult-onset autosomal dominant illness (IBMPFD) caused by mutations in the valosin-containing protein (VCP) on chromosome 9p21.1-p12. The penetrance of the gene is 82% for myopathy, 49% for Paget's disease, but may be as low as 30% for frontotemporal dementia. Modifier genes could account for decreased frontotemporal dementia penetrance. In this study apolipoprotein-E (APOE) was evaluated for this role in IBMPFD families based on its known modifier effect in Alzheimer's disease. METHODS: From a database of 231 members of 15 families, 174 had APOE genotype available for analysis. Logistic regressions on APOE genotype and frontotemporal dementia were performed, using appropriate covariates. RESULTS AND CONCLUSION: FTD was associated with APOE 4 genotype (P=0.0002), myopathy (P=0.0006), and age (P=0.01), but not microtubule associated protein tau (MAPT) H2 haplotype (P=0.5) or gender (0.09) after adjustment for membership in pedigrees with at least one APOE 4 genotype. These data suggest a potential link between APOE 4 genotype and the specific form of frontotemporal dementia found in IBMPFD. The molecular basis of this link bears further investigation. We did not observe an association of frontotemporal dementia and H2 MAPT haplotype."

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Brain cholesterol turnover required for geranylgeraniol production and learning in mice
Jorm AF, Mather KA, Butterworth P, Anstey KJ, Christensen H, Easteal S.
ORYGEN Research Centre, University of Melbourne, Parkville, VIC, Australia.
Neuropsychology (Jan 2007) 21(1): 1-8
[PubMed] [Authors contact]
 

Abstract: "There is evidence that the cognitive effects of Alzheimer's disease can be seen decades before disease diagnosis. If this is the case, then the apolipoprotein E (APOE) *E4 allele might be expected to have effects on cognitive functioning earlier in the life span. To assess such effects, the authors examined data on the *E4 allele and cognitive functioning from a population sample of 6,560 Caucasians covering the age groups of 20-24, 40-44, and 60-64 years. Participants were assessed on tests of episodic memory, working memory, mental speed, reaction time, and reading vocabulary. Although performance on all tests except reading vocabulary declined across age groups, there was no effect of the APOE *E4 allele at any age. These results indicate that APOE *E4 does not have preclinical effects early in the life span on these cognitive functions. Cognitive aging effects between the ages of 20 and 64 years must not be due to preclinical Alzheimer's disease."

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Polymorphisms of cholesterol metabolism genes CYP46 and ABCA1 and the risk of sporadic Alzheimer's disease in Chinese
Wang F, Jia J.
Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, Beijing 100 053, PR China; Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, PR China
Brain Res. (8 Feb 2007) [Epub ahead of print]
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Abstract: "Recent studies have demonstrated that cholesterol metabolism might play an important role in Alzheimer's disease (AD). Cholesterol 24-hydroxylase (CYP46) and ATP-binding cassette transporter A1 (ABCA1) have both been proposed to be involved in cholesterol metabolism in the brain. The purpose of this case-control study was to determine whether single nucleotide polymorphisms (SNPs) A-->G in the intron 2 of CYP46 gene and G-->A (R219K) in the exon 7 of ABCA1 gene are associated with sporadic AD in the Chinese Han population. Genotypes were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) in 168 sporadic AD patients and 215 controls. There was no significant difference in the genotype or allele frequencies for CYP46 gene between AD patients and controls. However, we found an obvious association between the polymorphism of ABCA1 gene and AD (chi(2)=8.230, P=0.016). The risk for AD was significantly decreased in K allele (RK+KK genotypes) (adjusted OR=0.57, 95% CI=0.36-0.91, P=0.019) or KK homozygote carriers (adjusted OR=0.40; 95% CI=0.21-0.77, P=0.006) compared with RR genotypes carriers. Our results do not support a genetic association between the intron 2 polymorphism of CYP46 gene and the risk of sporadic AD, but reveal that KK genotype or K allele of ABCA1 gene may have a protective effect for sporadic AD in Chinese."

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The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease
Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, Ring RH, Kirksey Y, Aschmies S, Xu J, Kubek K, Hirst WD, Gonzales C, Chen Y, Murphy E, Leonard S, Vasylyev D, Oganesian A, Martone RL, Pangalos MN, Reinhart PH, Jacobsen JS
Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA
Mol Cell Neurosci. (25 Jan 2007) [Epub ahead of print]
[PubMed] [Authors contact]
 

Abstract: "Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Abeta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Abeta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Abeta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Abeta42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Abeta40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Abeta42 and may represent a novel therapeutic approach to Alzheimer's disease."

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Cognitive impact of subcortical vascular and Alzheimer's disease pathology
Vinters HV.
Department of Neurology, University of Southern California, Los Angeles, USA
Ann Neurol. (Dec 2006) 60(6): 677-87
[PubMed] [Authors contact]
 

Abstract: "OBJECTIVE: To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimer's disease [AD]), cognitive status, and apolipoprotein E genotype. METHODS: We report clinicopathological correlations from 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease and AD. RESULTS: Thirty percent of the cases had significant cerebrovascular parenchymal pathology scores (CVDPS), 54% had significant AD pathology, and 18% had HS. In an ordinal logistic regression analysis that included interaction terms to assess the effects of each pathological variable when the other variables are interpolated to zero, each of the three pathology variables contributed independently to cognitive status: Braak and Braak stage odds ratio (OR) = 2.84 (95% confidence interval, 1.81-4.45), HS score OR = 2.43 (95% confidence interval, 1.01-5.85), and CVDPS OR = 1.02 (95% confidence interval, 1.00-1.04). Only Braak and Braak stage contributed to a global neuropsychological measure of cognitive impairment. Apolipoprotein E4 genotype was associated with Braak and Braak stage (OR, 1.31 [95% confidence interval, 1.03-1.68]), but not CVDPS or HS scores. INTERPRETATION: In this convenience sample enriched for subcortical ischemic vascular disease, HS was a common unsuspected neuropathological finding. Apolipoprotein E4 genotype was associated with cerebral amyloid angiopathy, but not HS or arteriosclerosis. When Braak and Braak stage was interpolated to zero, both CVDPS and HS contributed to cognitive impairment. However, advancing stages of AD pathology overwhelmed the effects of CVDPS and HS, to become the major determinant of dementia."

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Total cholesterol levels and the risk of mild cognitive impairment and Alzheimer's disease
Panza F, Capurso C, D'Introno A, Colacicco AM, De Candia D, Capurso A, Solfrizzi V.
J Am Geriatr Soc. (Jan 2007) 55(1): 133-135
[PubMed] [Authors contact]

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ApoE receptor 2 controls neuronal survival in the adult brain
Beffert U, Nematollah Farsian F, Masiulis I, Hammer RE, Yoon SO, Giehl KM, Herz J. 
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
Curr Biol. (19 Dec 2006) 16(24): 2446-2452
[PubMed] [Authors contact]
 

Abstract: "A central pathogenic feature of neurodegenerative diseases and neurotrauma is the death of neurons. A mechanistic understanding of the factors and conditions that induce the dysfunction and death of neurons is essential for devising effective treatment strategies against neuronal loss after trauma or during aging. Because Apolipoprotein E (ApoE) is a major risk factor for several neurodegenerative diseases, including Alzheimer's disease , a direct or indirect role of ApoE receptors in the disease process is likely. Here we have used gene targeting in mice to investigate possible roles of ApoE receptors in the regulation of neuronal survival. We demonstrate that a differentially spliced isoform of an ApoE receptor, ApoE receptor 2 (Apoer2), is essential for protection against neuronal cell loss during normal aging. Furthermore, the same splice form selectively promotes neuronal cell death after injury through mechanisms that may involve serine/threonine kinases of the Jun N-terminal kinase (JNK) family. These findings raise the possibility that ApoE and its receptors cooperatively regulate common mechanisms that are essential to neuronal survival in the adult brain."

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Lipid-induced beta-amyloid peptide assemblage fragmentation
Widenbrant MJ, Rajadas J, Sutardja C, Fuller GG.
Department of Chemical Engineering, Stanford University, Stanford, CA, USA
Biophys J (1 Dec 2006) 91(11): 4071-80
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Abstract: "Alzheimer's disease is the most common cause of dementia and is widely believed to be due to the accumulation of beta-amyloid peptides (Abeta) and their interaction with the cell membrane. Abetas are hydrophobic peptides derived from the amyloid precursor proteins by proteolytic cleavage. After cleavage, these peptides are involved in a self-assembly-triggered conformational change. They are transformed into structures that bind to the cell membrane, causing cellular degeneration. However, it is not clear how these peptide assemblages disrupt the structural and functional integrity of the membrane. Membrane fluidity is one of the important parameters involved in pathophysiology of disease-affected cells. Probing the Abeta aggregate-lipid interactions will help us understand these processes with structural detail. Here we show that a fluid lipid monolayer develop immobile domains upon interaction with Abeta aggregates. Atomic force microscopy and transmission electron microscopy data indicate that peptide fibrils are fragmented into smaller nano-assemblages when interacting with the membrane lipids. Our findings could initiate reappraisal of the interactions between lipid assemblages and Abeta aggregates involved in Alzheimer's disease."

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Cathepsin D-mediated proteolysis of apolipoprotein E: possible role in Alzheimer's disease
Zhou W, Scott SA, Shelton SB, Crutcher KA.
Department of Neurosurgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0515, USA
Neuroscience (Dec 2006) 143(3): 689-701. ePpub 25 Sept 2006
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Abstract: "Proteolysis of apolipoprotein E (apoE) may be involved in the pathogenesis of Alzheimer's disease (AD). We previously identified aspartic protease(s) as possibly contributing to the proteolysis of apoE in human brain homogenates. The current study used biochemical and immunohistochemical methods to examine whether cathepsin D (catD) and cathepsin E (catE), candidate aspartic proteases, may be involved in apoE proteolysis. CatD was found to proteolyze both lipid-free recombinant full-length human apoE and lipidated human plasma full-length apoE (apoE4/dipalmitoylphosphatidylcholine-reconstituted discs). CatE was found to proteolyze lipid-free recombinant human apoE to a much greater extent than lipidated apoE. This proteolysis, as well as proteolysis of human apoE added to brain homogenates from apoE-deficient mice, was inhibited by pepstatin A (an aspartic protease inhibitor), but not by phenylmethanesulfonyl fluoride (a serine protease inhibitor). The major apoE fragment obtained with catD included the receptor-binding domain and had an apparent molecular weight similar to that found in human brain homogenates. There was little immunoreactivity for catE in AD brain tissue sections. In contrast, qualitative and quantitative analyses of immunostained sections of the frontal cortex revealed that catD and apoE are colocalized in a subset of predominantly dense-core neuritic plaques and in some neurofibrillary tangles. A positive correlation was observed between estimated duration of illness and the percentage of apoE-positive plaques that were also catD-positive. These results suggest that aspartic proteases, catD in particular, may be involved in proteolysis of apoE and perhaps contribute to the generation of apoE fragments previously implicated in AD pathology."

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