NOTEWORTHY ARTICLES 2006

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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Noteworthy pages readership 1 January 2003 - 1 February 2005: 4742

Simvastatin enhances learning and memory independent of amyloid load in mice
Li L, Cao D, Kim H, Lester R, Fukuchi K.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
Ann Neurol. (Dec 2006) 60(6): 729-39
[PubMed] [Authors contact]
 

Article Abstract: "OBJECTIVE: Normal aging is often associated with a decline in learning and memory functions. This decline is manifested to a much greater extent in Alzheimer's disease. Recent studies have indicated statins, a class of cholesterol-lowering drugs, as a potential therapy for Alzheimer's disease. Our objective was to determine whether administering a statin drug (simvastatin) would protect against the development of behavioral deficits in an established mouse model of Alzheimer's disease. METHODS: Tg2576 mice and their nontransgenic littermates were treated with simvastatin and assessed by behavioral tests and biochemical analyses. RESULTS: Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice. Moreover, levels of amyloid beta protein in the brains of treated mice did not differ from those of untreated mice. Simvastatin treatment was associated with increased expression levels of protein kinase B (Akt) and endothelial nitric oxide synthase in the mouse brain. INTERPRETATION: Our findings demonstrate that the effects of simvastatin on learning and memory are independent of amyloid beta protein levels. The mechanisms by which simvastatin exerts its beneficial effects may be related to modulation of signaling pathways in memory formation."

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Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations
Klarner B, Klunemann HH, Lurding R, Aslanidis C, Rupprecht R.
Institute for Psychogerontology, University of Erlangen-Nuremberg, Erlangen, Germany
Inherit Metab Dis. (Feb 2007) 30(1): 60-7. ePub 2006 Dec 11
[PubMed] [Authors contact]
 

Article Abstract: "Niemann-Pick type C disease is a fatal neurovisceral disorder linked to dysregulation in cholesterol processing. A medication for this disease is currently being tested in clinical trials. However, there is a lack of information on neuropsychological testing parameters for this disease. One aim of this pilot study was to evaluate a test battery that could be used to assess cognitive deficits in different stages of the disease. A second aim was to determine whether specific functional deficits are associated with certain disease stages. Eight men and two women (19-40 years of age) harbouring mutations in the gene coding for the cholesterol trafficking protein NPC1 were put through the same test battery independently of their disease stage. The external staging criterion was based on a five-step clinical scale. Trail Making tests A & B and verbal fluency were sensitive indicators at early stages of NPC. Corsi Block-Tapping, Mini Mental Status, Find Similarities and Clock Drawing showed abnormal results in patients with advanced disease. The Grooved Pegboard, Trail Making and Mosaic tests were unsuitable in advanced disease due to impaired fine motor skills. We observed that visuospatial working memory was less affected by the neurodegenerative process than verbal working memory. The series of tests used here could be supplemented by the severe impairment battery and Raven matrices tests for patients with advanced disease."

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APOE genotype and cholesterol levels in lewy body dementia and Alzheimer disease: investigating genotype-phenotype effect on disease risk
WBorroni B, Grassi M, Costanzi C, Archetti S, Caimi L, Padovani A.
Centre for Ageing Brain and Dementia, Department of Neurology, the III Laboratory of Biotechnology and Department of Biochemistry, University of Brescia, Brescia, Italy.
Am J Geriatr Psychiatry (Dec 2006) 14(12): 1022-1031. ePub 6 Sept 2006
[PubMed] [Authors contact]
 

Abstract: "BACKGROUND: APOE is the most recognized genetic risk factor for sporadic late-onset Alzheimer disease (AD). The role of APOE genotype in Lewy body dementia (LBD) is still unknown as well as the relationship between APOE genotype and cholesterol levels. OBJECTIVE: The objective of this study was to explore the association between APOE genotype and cholesterol levels in patients with LBD and those with AD. METHODS: Eighty-two patients with LBD were consecutively enrolled as well as a comparable number of patients with AD and comparison group. Each subject underwent a clinical and neuropsychologic evaluation and APOE genotyping. RESULTS: The distribution of APOE genotypes significantly differed between AD and LBD cases compared with the comparison group, with the APOE epsilon4+ (epsilon4+/epsilon4 + or epsilon4+/epsilon4-) genotype more frequent in patient subgroups. Different models have been fitted, and total APOE epsilon4-hypercholesterolemia complete interaction effect was claimed in predicting their relationship on disease outcome. Subjects with hypercholesterolemia and heterozygous for APOE epsilon4 allele had more than threefold risk to develop AD compared both with the comparison group and with those with LBD. The risk to develop AD in hypercholesterolemic and APOE epsilon4 homozygous subjects was 13-fold compared with the comparison group and those with LBD. Conversely, there was not evidence for APOE epsilon4-hypercholesterolemia complete interaction effect in LBD and in the comparison group. CONCLUSIONS: This study highlighted that APOE is a risk factor not only for AD, but also for LBD, and that the APOE-cholesterol pathway differently affects AD and LBD. This approach may aid the search for the identification of an interactive effect of APOE genotype and modifiable risk factors, i.e., hypercholesterolemia, eventually resulting in individualized and effective cholesterol-lowering therapy in at-risk subjects."

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Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis
Carter CJ
Neurochem Int. (Jan 2007) 50(1): 12-38, ePpub 12 Sep 2006.
[PubMed] [Authors contact]
 

Article Abstract: "Polymorphic genes associated with Alzheimer's disease delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer's disease, may play a major role in its pathology. Many other genes associated with Alzheimer's disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer's disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer's disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to the same signaling pathway, the risk associated with multigenic disease is better related to the integrated effects of multiple polymorphisms of genes within the same pathway than to variants in any single gene [Wu, X., Gu, J., Grossman, H.B., Amos, C.I., Etzel, C., Huang, M., Zhang, Q., Millikan, R.E., Lerner, S., Dinney, C.P., Spitz, M.R., 2006. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am. J. Hum. Genet. 78, 464-479.]. Thus, the fact that Alzheimer's disease susceptibility genes converge on a clearly defined signaling network has important implications for genetic association studies."

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Cholesterol distribution, not total levels, correlate with altered amyloid precursor protein processing in statin-treated mice
Burns MP, Igbavboa U, Wang L, Wood WG, Duff K.
Center for Dementia Research, Nathan S. Kline Institute/New York University, Orangeburg, NY 10962, USA.
Neuromolecular Med. (2006) 8(3): 319-328.
[PubMed] [Authors contact]
 

Abstract: "There are now a number of studies that suggest that cholesterol might regulate the processing of the amyloid precursor protein to form the neurotoxic peptide Abeta. This research has opened the possibility that cholesterol-lowering drugs might be efficacious as anti-Abeta drugs for use in Alzheimer's disease. The use of HMG-CoA reductase inhibitors (commonly called statins) in vitro and in vivo has proven them to be Abeta-lowering agents, however, the mechanism of action of these drugs is not yet known. One possible mechanism is that they reduce Abeta levels indirectly by reducing cholesterol in the central nervous system (CNS). In this study, we administered three different statins (simvastatin, lovastatin, and atorvastatin) to nontransgenic mice. We found that all three compounds had similar effects on Abeta, reducing both Abeta40 and Abeta42. The statins decreased beta-cleaved C-terminal fragment (CTF) although having no effect on alpha-CTF levels. However, the drugs did not have a similar effect on cholesterol in the CNS. Only lovastatin significantly reduced total cholesterol in isolated plasma membranes. As cholesterol is not distributed evenly in the plasma membrane, we examined bilayer distribution of cholesterol and found that all three statins caused CNS cholesterol to translocate from the cytofacial leaflet to the exofacial leaflet. This data suggests that cholesterol distribution and not total cholesterol levels may be important to Abeta production in the CNS."

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Localization of synaptic proteins involved in neurosecretion in different membrane microdomains
Taverna E, Saba E, Linetti A, Longhi R, Jeromin A, Righi M, Clementi F, Rosa P.
CNR Institute of Neuroscience, Department of Medical Pharmacology, University of Milan, Milan, Italy.
J Neurochem (Feb 2007) 100(3): 664-677 (ePub 1 Nov 2006)
[PubMed] [Authors contact]
 

Abstract: "A number of proteins and signalling molecules modulate voltage-gated calcium channel activity and neurosecretion. As recent findings have indicated the presence of Ca(v)2.1 (P/Q-type) channels and soluble N-ethyl-maleimide-sensitive fusion protein attachment protein receptors (SNAREs) in the cholesterol-enriched microdomains of neuroendocrine and neuronal cells, we investigated whether molecules known to modulate neurosecretion, such as the heterotrimeric G proteins and neuronal calcium sensor-1 (NCS-1), are also localized in these microdomains. After immuno-isolation, flotation gradients from Triton X-100-treated synaptosomal membranes revealed the presence of different detergent-resistant membranes (DRMs) containing proteins of the exocytic machinery (Ca(v)2.1 channels and SNAREs) or NCS-1; both DRM subtypes contained aliquots of heterotrimeric G protein subunits and phosphatidylinositol-4,5-bisphosphate. In line with the biochemical data, confocal imaging of immunolabelled membrane sheets revealed the localization of SNARE proteins and NCS-1 in different dot-like structures. This distribution was largely impaired by treatment with methyl-beta-cyclodextrin, thus suggesting the localization of all three proteins in cholesterol-dependent domains. Finally, bradykinin (which is known to activate the NCS-1 pathway) caused a significant increase in NCS-1 in the DRMs. These findings suggest that different membrane microdomains are involved in the spatial organization of the complex molecular network that converges on calcium channels and the secretory machinery."

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Mutant presenilin 2 causes abnormality in the brain lipid profile in the development of Alzheimer's disease
Nguyen HN, Son DJ, Lee JW, Hwang DY, Kim YK, Cho JS, Lee US, Yoo HS, Moon DC, Oh KW, Hong JT.
College of Pharmacy and CBITRC, Chungbuk Natio nal University, Cheongju 361-763, Korea
Arch Pharm Res (Oct 2006) 29(10): 884-9
[PubMed] [Authors contact]
 

Article Abstract: "Mutation in the presenilin 2 (PS2mt) is known to be one of factors involved in the development of Alzheimer's disease (AD). It was recently revealed that an abnormality of lipid metabolism is a phenomenon occurring in AD. Therefore, the aim of this study was to investigate the potential relationship between the mutation of PS2 and alterations of the lipid profile within the brain. The results showed there increases in the levels of cholesterol, low density lipoprotein and triglyceride, but a decrease in the level of high density lipoprotein in brain tissues expressing mutant PS2. These findings indicated that PS2mt is involved in the abnormalities of the lipid profile, which could cause or result in the development of AD."

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A polymorphism in lipoprotein lipase affects the severity of Alzheimer's disease pathophysiology
Blain JF, Aumont N, Theroux L, Dea D, Poirier J
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
Eur J Neurosci. (Sep 2006) 24(5): 1245-51
[PubMed] [Authors contact]
 

Article Abstract: "Emerging evidences indicate a role for lipoprotein lipase (LPL) in degenerative states. Genetic variations in the LPL gene were previously associated to lipid imbalance and coronary artery disease (CAD) risk and severity, a condition that shares pathological features with common Alzheimer's disease (AD). To evaluate whether these genetic variations associate with the risk and pathophysiology of common AD, autopsy-confirmed patients (242 controls, 153 AD) were genotyped for a PvuII single nucleotide polymorphism (SNP; rs285; referred to as the P+ allele) of LPL. Brain LPL mRNA levels, cholesterol levels, amyloid concentration, senile plaques and neurofibrillary tangles density counts were measured and contrasted with specific LPL genotypes. When adjusted for age and sex, homozygosity for the P+ allele resulted in an odds ratio of 2.3 for the risk of developing AD. More importantly, we report that the presence of the P+ allele of LPL significantly affects its mRNA expression level (n = 51; P = 0.026), brain tissue cholesterol levels (n = 55; P = 0.0013), neurofibrillary tangles (n = 52; P = 0.025) and senile plaque (n = 52; P = 0.022) densities. These results indicate that a common polymorphism in the lipoprotein lipase gene modulates the risk level for sporadic AD in the eastern Canadian population but more importantly, indirectly modulates the pathophysiology of the brain in autopsy-confirmed cases."

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Functional role of the low-density lipoprotein receptor-related protein in Alzheimer's disease
Waldron E, Jaeger S, Pietrzik CU
Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, Mainz, Germany
Neurochem Int (May 2005) 46(6): 489-99
[PubMed] [Authors contact]
 

Abstract: "Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by neuronal loss, neurofibrillary tangle formation and the extracellular deposition of amyloid-beta (Abeta) plaques. The amyloid precursor protein (APP) and the enzymes responsible for Abeta generation seem to be the base elements triggering the destructive processes. Initially, the low-density lipoprotein receptor-related protein (LRP) was genetically linked to AD and later it emerged to impact on many fundamental events related to this disease. LRP is not only involved in Abeta clearance but is also the major receptor of several AD-associated ligands, e.g. apolipoprotein E and alpha(2)-macroglobulin. APP processing is mediated by LRP on many levels. Enhanced APP internalization through LRP decreases cell surface APP levels and thereby reduces APP shedding. As a consequence of increased APP internalization LRP enhances Abeta secretion. These effects could be attributed to the cytoplasmic tails of LRP and APP. The receptors bind via their NPXY motifs to the two PID domains of FE65 and form a tripartite complex. However, it appears that the second NPVY motif of LRP is the one responsible for the observed influence over APP metabolism. A more in-depth knowledge of the mechanisms regulating APP cleavage may offer additional targets for therapeutic intervention."

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Docosahexaenoic acid-induced protective effect against impaired learning in amyloid beta-infused rats is associated with increased synaptosomal membrane fluidity
Hashimoto M, Hossain S, Shimada T, Shido O.
Department of Environmental Physiology, Shimane University, Faculty of Medicine, Izumo, Japan.
Clin Exp Pharmacol Physiol. (Oct 2006) 33(10): 934-9
[PubMed] [Authors contact]
 

Abstract: "In the present study, we investigated the relationship between the docosahexaenoic acid (DHA)-induced protection of learning deficit of amyloid beta(1-40)-infused Alzheimer's disease (AD) model rats and changes in synaptosomal plasma membrane fluidity of the cerebral cortex. Synaptosomal membrane lateral and rotational fluidity were measured using pyrene excimer spectroscopy and fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH), respectively. Avoidance learning ability, as assessed by a two-way active avoidance paradigm, decreased significantly in the AD model rats. Pyrene-determined annular/non-annular fluidity ratio and the DPH-determined bulk fluidity of the synaptosomal plasma membrane decreased in the amyloid beta(1-40)-infused rats. Oral pre-administration of DHA (300 mg/kg per day for 12 weeks) significantly increased both lateral and rotational fluidity. The synaptosomal membrane DHA content increased and the cholesterol to phospholipid molar ratio and lipid peroxidation decreased. The annular to non-annular fluidity ratio of the synaptic plasma membrane was positively correlated with total avoidance learning. The present results indicate that DHA-induced alterations in synaptic plasma membrane fluidity may contribute to the synaptic plasma membrane-related functions that constitute avoidance learning-related memory in amyloid beta(1-40)-infused rats."

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Statins of Different Brain Penetrability Differentially Affect CSF PLTP Activity
Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ
Department of Medicine, University of Washington School of Medicine, Seattle, Wash., USA
Neurochem Int. (7 Sep 2006) (aPub ahead of print)
[PubMed] [Authors contact]
 

Article Abstract: "Background/Aims: Phospholipid transfer protein (PLTP) and apolipoprotein E (apoE) are key proteins involved in lipoprotein metabolism in the peripheral circulation and in the brain. Several epidemiological studies suggested that use of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduces risk of Alzheimer's disease (AD). However, the effects of statins of differing blood-brain barrier (BBB) penetrability on brain-derived molecules in cognitively normal individuals are largely unknown. Methods: To assess the effect of statins on these indices as a function of BBB penetration, cerebrospinal fluid (CSF) and plasma PLTP activity and apoE concentration were measured in cognitively intact, modestly hypercholesterolemic adults randomly allocated to treatment with either pravastatin, which does not penetrate BBB (80 mg/day, n = 13), or simvastatin, which penetrates BBB (40 mg/day, n = 10). Results: Simvastatin significantly increased CSF PLTP activity (p = 0.005). In contrast, pravastatin had no such effect. In the pravastatin-treated group, CSF apoE concentration decreased significantly (p = 0.026), while the simvastatin-treated group showed a tendency towards lower CSF apoE levels, with CSF apoE concentration lowered in 8 of 10 subjects. Conclusion: Our data indicate that statins differentially affect two key lipid transfer proteins in the brain, and that effect on PLTP activity depends on statin BBB penetrability."

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Synaptic proteins associate with a sub-set of lipid rafts when isolated from nerve endings at physiological temperature
Gil C, Cubi R, Blasi J, Aguilera J.
Departament de Bioquimica i Biologia Molecular and Institut de Neurociencies, Universitat Autonoma de Barcelona, Bellaterra 08193, Barcelona, Spain.
Biochem Biophys Res Commun. (6 Oct 2006) 348(4): 1334-42
[PubMed] [Authors contact]
 

Abstract: "Although the high presence of cholesterol in nerve terminals is well documented, specific roles of this lipid in transmitter release have remained elusive. Since cholesterol is a highly enriched component in the membrane microdomains known as lipid rafts, it is probable that these domains are very important in synaptic function. The extraction of lipid rafts using Brij 98 at 37 degrees C avoids the formation of nonspecific membrane aggregates at low temperature, allowing the isolation of more physiologically relevant lipid rafts. In the present work, we examine, by means of buoyancy analysis in sucrose gradients after solubilization of the membranes with Brij 98 or with Lubrol WX, the presence of proteins involved in exocytosis in detergent-resistant membranes (DRM) using rat brain synaptosomes as a neurological model. Significant proportions of the proteins tested in the present work, which are involved in neurotransmitter release, are found in Brij 98 raft fractions, demonstrating that significant pools of synaptic proteins are segregated in specific parts of the membrane at physiological temperature. On the other hand, Lubrol WX is unable to solubilize the major fraction of the proteins tested. Treatment of synaptosomes with methyl-beta-cyclodextrin (mbetaCD) causes alteration in the buoyancy properties of proteins initially present in Brij- as well as in Lubrol-resistant membranes, indicating the cholesterol-dependency of both kinds of microdomains. Finally, we detect the depolarization-induced enhancement of the cholesterol-dependent association of syntaxin 1 with Brij 98-rafts, under the same conditions in which prolonged neurotransmitter release is stimulated."

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The adult form of Niemann-Pick disease type C
Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, Sedel F.
Assistance Publique-Hopitaux de Paris, Federation des maladies du systeme nerveux, Paris, France.
Brain (26 September 2006) ePub ahead of print
[PubMed] [Authors contact]
 

Abstract: "Niemann-Pick disease type C (NPC) is a fatal neurovisceral lipid storage disease of autosomal inheritance resulting from mutations in either the NPC1 (95% of families) or NPC2 gene. The encoded proteins appear to be involved in lysosomal/late endosomal transport of cholesterol, glycolipids and other molecules but their exact function is still unknown. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. Based upon a comprehensive study of 13 unrelated adult patients diagnosed in France over the past 20 years as well as the analysis of the 55 other cases published since 1969, we have attempted to delineate the major clinical, radiological, biochemical and genotypic characteristics of adult NPC. Overall, mean age at onset (+/-SD) of neuropsychiatric symptoms was 25 +/- 9.7 years. The diagnosis of NPC was established after a mean delay of 6.2 +/- 6.4 years and the mean age at death (calculated from 20 cases) was 38 +/- 10.2 years. Major clinical features included cerebellar ataxia (76%), vertical supranuclear ophthalmoplegia (VSO, 75%), dysarthria, (63%), cognitive troubles (61%), movement disorders (58%), splenomegaly (54%), psychiatric disorders (45%) and dysphagia (37%). Less frequent signs were epilepsy and cataplexy. During the course of the disease, clinical features could be subdivided into (i) visceral signs (hepatomegaly or splenomegaly), (ii) cortical signs (psychiatric cognitive disorders and epilepsy); and (iii) deep brain signs (VSO, ataxia, movement disorders, dysarthria, dysphagia, cataplexy) which exhibited different evolution patterns. Asymptomatic and non-evolutive visceral signs were often noticed since early childhood (38.5% of our patients), followed by mild cortical signs in childhood (learning difficulties) and early adulthood (62% of cases among which 38% were psychiatric disorders). Deep brain signs were observed in 96% of patients and were usually responsible for death. In general, there was a good correlation between clinical signs and the localization of brain atrophy on MRI. The 'variant' biochemical phenotype characterized by mild abnormalities of the cellular trafficking of endocytosed cholesterol was over-represented in the adult form of NPC and seemed associated with less frequent splenomegaly in childhood and lesser psychiatric signs. Involvement of the NPC1 gene was shown in 33 families and of the NPC2 gene in one. Improving the knowledge of the disease among psychiatrists and neurologists appears essential since emerging treatments should be more efficient at the visceral or cognitive/psychiatric stages of the disease, before the occurrence of widespread deep brain neurological lesions."

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Estrogen modulates place learning through estrogen receptors in the hippocampus
Zurkovsky L, Brown SL, Korol DL.
Neuroscience Program, University of Illinois, Champaign, IL 61820, USA
Exp Gerontol (20 November 2005) ePub ahead of prin
Neurobiol Learn Mem (Nove 2006) 86(3): 336-43. (ePub 18 Sept 2006)
[PubMed] [Authors contact]
 

Abstract: "Moderate elevations in circulating estradiol enhance learning in tasks that tap place learning strategies such as those requiring the use of extramaze cues. Use of place learning strategies is particularly impaired by damage to the hippocampus, a structure shown to be sensitive to estrogen treatments. We have shown that direct estrogen infusions into the dorsal hippocampus, and not the dorsolateral striatum, enhance place learning, suggesting that the hippocampus may be an important modulatory site for the effects of estrogen on place learning. The current experiment tested whether the hippocampus is indeed a critical site of estrogen modulation through classical estrogen receptors. Young adult female Sprague-Dawley rats were ovariectomized for 21 days and given systemic injections (0.1ml) of sesame oil (OIL) or 10mug of 17beta-estradiol-benzoate (E2), 48 and 24h before being trained on a place task. Twenty-four hours prior to the first systemic injection, separate groups of rats received bilateral hippocampal implants of either the antiestrogen ICI 182,780 (ICI) or cholesterol vehicle. Implants were maintained until and throughout training. Intrahippocampal ICI reversed the enhancement in place learning seen with systemic E2 treatment. Unexpectedly, intrahippocampal ICI in OIL-treated rats also enhanced place learning. These data suggest that ICI may have some mixed agonist and antagonist effects in the hippocampus and that estrogen enhances place learning through activation of estrogen receptors located in the hippocampus."

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Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction
Willmann R, Pun S, Stallmach L, Sadasivam G, Santos AF, Caroni P, Fuhrer C
Department of Neurochemistry, Brain Research Institute, University of Zurich, Zurich, Switzerland
EMBO J. (6 Sep 2006) 25(17): 4050-60
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Abstract: "Stabilization and maturation of synapses are important for development and function of the nervous system. Previous studies have implicated cholesterol-rich lipid microdomains in synapse stabilization, but the underlying mechanisms remain unclear. We found that cholesterol stabilizes clusters of synaptic acetylcholine receptors (AChRs) in denervated muscle in vivo and in nerve-muscle explants. In paralyzed muscles, cholesterol triggered maturation of nerve sprout-induced AChR clusters into pretzel shape. Cholesterol treatment also rescued a specific defect in AChR cluster stability in cultured src(-/-);fyn(-/-) myotubes. Postsynaptic proteins including AChRs, rapsyn, MuSK and Src-family kinases were strongly enriched in lipid microdomains prepared from wild-type myotubes. Microdomain disruption by cholesterol-sequestering methyl-beta-cyclodextrin disassembled AChR clusters and decreased AChR-rapsyn interaction and AChR phosphorylation. Amounts of microdomains and enrichment of postsynaptic proteins into microdomains were decreased in src(-/-);fyn(-/-) myotubes but rescued by cholesterol treatment. These data provide evidence that cholesterol-rich lipid microdomains and SFKs act in a dual mechanism in stabilizing the postsynapse: SFKs enhance microdomain-association of postsynaptic components, whereas microdomains provide the environment for SFKs to maintain interactions and phosphorylation of these components."

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Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice
Oksman M, Iivonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lutjohann D, Hartmann T, Tanila H
Department of Neuroscience and Neurology, University of Kuopio, Finland
Neurobiol Dis. (Sep 2006) 23(3): 563-72
[PubMed] [Authors contact]
 

Abstract: "The present study assessed the influence of dietary lipids on accumulation of amyloid beta-peptide (Abeta) in the brain. Seven experimental diets with varying n-6/n-3-ratio, saturated and polyunsaturated fatty acid and cholesterol contents were fed to transgenic APPswe/PS1dE9 mice for 3-4 months beginning at a young adult age (6 months). Hippocampal Abeta levels were determined with ELISA and plaque load by using immunocytochemistry. A typical Western diet with 40% saturated fatty acids and 1% of cholesterol increased, while diets supplemented with docosahexaenoic acid (DHA) decreased Abeta levels compared to regular (soy oil based) diet. DHA diet also decreased the number of activated microglia in hippocampus and increased exploratory activity of transgenic mice, but did not improve their spatial learning in the water maze. The favorable effect of DHA on Abeta production was verified in two different cell lines. Regulation of dietary lipid intake may offer a new tool to reduce the risk of Alzheimer's disease at the population level."

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Cholesterol-enriched diet affects spatial learning and synaptic function in hippocampal synapses
Dufour F, Liu QY, Gusev P, Alkon D, Atzori M
Blanchette Rockefeller Neurosciences Institute, 9601 Medical Center Drive, Rockville, MD 20850, USA
Brain Res. (4 August 2006) 1103(1): 88-98
[PubMed] [Authors contact]
 

Abstract: "The aim of the present study was to determine the effect of a cholesterol-rich diet on learning performance and monitor possible related changes in synaptic function. To this purpose, we compared controls with rats fed with a cholesterol-enriched diet (CD). By using a Morris water-maze paradigm, we found that CD rats learned a water-maze task more quickly than rats fed with a regular diet (RD). A longer period of this diet tended to alter the retention of memory without affecting the improvement in the acquisition of the task. Because of the importance of the hippocampus in spatial learning, we hypothesized that these behavioral effects of cholesterol would involve synaptic changes at the hippocampal level. We used whole-cell patch-clamp recording in the CA1 area of a hippocampal rat slice preparation to test the influence of the CD on pre- and postsynaptic function. CD rats displayed an increase in paired-pulse ratio in both glutamatergic synapses (+48 +/- 9%) and GABAergic synapses (+41 +/- 8%), suggesting that the CD induces long-lasting changes in presynaptic function. Furthermore, by recording NMDA-receptor-mediated currents (I(NMDA)) and AMPA-receptor-mediated currents (I(AMPA)) in the same set of cells we found that CD rats display a lower I(NMDA)/I(AMPA) ratio (I(NMDA)/I(AMPA) = 0.75 +/- 0.32 in RD versus 0.10 +/- 0.03 in CD), demonstrating that cholesterol regulates also postsynaptic function. We conclude that a cholesterol-rich diet affects learning speed and performance, and that these behavioral changes occur together with robust, long-lasting, synaptic changes at both the pre- and postsynaptic level."

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Quantitative proteomic analysis of detergent-resistant membranes from chemical synapses: Evidence for cholesterol as spatial organizer of synaptic vesicle cycling
Jia J, Lamer S, Schuemann M, Schmidt M, Krause E, Haucke V
Membrane Biochemistry, Freie Univ Berlin, Berlin 14195
Mol Cell Proteomics (21 July 2006) ePpub ahead of print
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Abstract: "Synaptic vesicles (SVs) in the central nervous system upon stimulation undergo rapid calcium-triggered exo-endocytic cycling within the nerve terminal which at least in part depends on components of the clathrin- and dynamin-dependent endocytosis machinery. How exocytic SV fusion and endocytic retrieval are temporally and spatially coordinated is still an open question. One possibility is that specialized membrane microdomains characterized by their high content in membrane cholesterol may assist in the spatial coordination of synaptic membrane protein recycling. Quantitative proteomic analysis of detergent-resistant lipid microdomains (DRMs) isolated from rat brain synapses or cholesterol-depleted control samples by liquid chromatography tandem mass spectrometry identified a total of 159 proteins. Among these 122 proteins were classified as cholesterol-dependent DRM or DRM-associated proteins, many of which with proven or hypothesized functions in exo-endocytic vesicle cycling including clathrin, the clathrin adaptor complex AP-2, and a variety of SV proteins. In agreement with this SV membrane and endocytic proteins display a partial resistance to extraction with cold Triton X-100 in cultured rat hippocampal neurons where they co-localize with labeled cholera toxin B, a marker for cholesterol-enriched DRMs. Moreover, SV proteins form cholesterol-dependent complexes in CHAPS-extracted synaptic membrane lysates. Our combined data suggest that lipid microdomains may act as spatial coordinators for exo-endocytic vesicle cycling at synapses."

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Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family
Cam JA, Bu G
Departments of Pediatrics, and Cell Biology & Physiology, Washington University School of Medicine, St, Louis, Missouri 63110, USA
Mol Neurodegener. (18 August 2006) 1: 8
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Abstract: "Amyloid-beta peptide (Abeta) accumulation in the brain is an early, toxic event in the pathogenesis of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of a transmembrane protein, beta-amyloid precursor protein (APP), by beta- and gamma-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Abeta. Recent studies have shown that members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apolipoprotein E (apoE) receptor 2, interact with APP and regulate its endocytic trafficking. Another common feature of these receptors is their ability to bind apoE, which exists in three isoforms in humans and the presence of the epsilon4 allele represents a genetic risk factor for AD. In this review, we summarize the current understanding of the function of these apoE receptors with a focus on their role in APP trafficking and processing. Knowledge of the interactions between these distinct low-density lipoprotein receptor family members and APP may ultimately influence future therapies for AD."

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Serum amyloid A (SAA)-induced remodeling of CSF-HDL
Miida T, Yamada T, Seino U, Ito M, Fueki Y, Takahashi A, Kosuge K, Soda S, Hanyu O, Obayashi K, Miyazaki O, Okada M
Division of Clinical Preventive Medicine, Department of Community Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Niigata, Niigata 951-8510, Japan
Biochim Biophys Acta. (April 2006) 1761(4): 424-433
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Abstract: "Inflammation is a risk factor for Alzheimer's disease. Serum amyloid A (SAA) is an acute phase protein that dissociates apolipoprotein AI (apoAI) from plasma HDL. In cerebrospinal fluid (CSF), the SAA concentration is much higher in subjects with Alzheimer's disease than in controls. CSF-HDL is rich in apoE, which plays an important role as a ligand for lipoprotein receptors in the central nervous system (CNS). To clarify whether SAA dissociates apoE from CSF-HDL, we added recombinant SAA to CSF and determined the apoE distribution in the CSF using native two-dimensional gel electrophoresis. We found that SAA dissociated apoE from CSF-HDL in a dose-dependent manner. This effect was more evident in apoE4 carriers than in apoE3 or apoE2 carriers. After a 24-h incubation at 37 degrees C, SAA continuously dissociated apoE from CSF-HDL. Amyloid beta (Abeta) fragments (1-42) were bound to large CSF-HDL but not to apoE dissociated by SAA. In conclusion, SAA dissociates apoE from CSF-HDL. We postulate that inflammation in the CNS may impair Abeta clearance due to the loss of apoE from CSF-HDL."

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Molecular composition of the endocannabinoid system at glutamatergic synapses
Katona I, Urban GM, Wallace M, Ledent C, Jung KM, Piomelli D, Mackie K, Freund TF
Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary
J Neurosci (24 May 2006) 26(21): 5628-37
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Abstract: "Endocannabinoids play central roles in retrograde signaling at a wide variety of synapses throughout the CNS. Although several molecular components of the endocannabinoid system have been identified recently, their precise location and contribution to retrograde synaptic signaling is essentially unknown. Here we show, by using two independent riboprobes, that principal cell populations of the hippocampus express high levels of diacylglycerol lipase alpha (DGL-alpha), the enzyme involved in generation of the endocannabinoid 2-arachidonoyl-glycerol (2-AG). Immunostaining with two independent antibodies against DGL-alpha revealed that this lipase was concentrated in heads of dendritic spines throughout the hippocampal formation. Furthermore, quantification of high-resolution immunoelectron microscopic data showed that this enzyme was highly compartmentalized into a wide perisynaptic annulus around the postsynaptic density of axospinous contacts but did not occur intrasynaptically. On the opposite side of the synapse, the axon terminals forming these excitatory contacts were found to be equipped with presynaptic CB1 cannabinoid receptors. This precise anatomical positioning suggests that 2-AG produced by DGL-alpha on spine heads may be involved in retrograde synaptic signaling at glutamatergic synapses, whereas CB1 receptors located on the afferent terminals are in an ideal position to bind 2-AG and thereby adjust presynaptic glutamate release as a function of postsynaptic activity. We propose that this molecular composition of the endocannabinoid system may be a general feature of most glutamatergic synapses throughout the brain and may contribute to homosynaptic plasticity of excitatory synapses and to heterosynaptic plasticity between excitatory and inhibitory contacts."

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Binding of alpha-synuclein affects the lipid packing in bilayers of small vesicles
Kamp F, Beyer K
Laboratory of Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilian University, 80336 Munich, Germany
J Biol Chem (7 April 2006) 281(14): 9251-9259
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Abstract: "The intracellular deposition of fibrillar aggregates of alpha-synuclein is a characteristic feature of Parkinson disease. Alternatively, as a result of its unusual conformational plasticity, alpha-synuclein may fold into an amphipathic helix upon contact with a lipid-water interface. Using spin label ESR and fluorescence spectroscopy, we show here that alpha-synuclein affects the lipid packing in small unilamellar vesicles. The ESR hyperfine splittings of spin-labeled phospholipid probes revealed that alpha-synuclein induces chain ordering at carbon 14 of the acyl chains below the chain melting phase transition temperature but not in the liquid crystalline state of electroneutral vesicle membranes. Binding of alpha-synuclein leads to an increase in the temperature and cooperativity of the phase transition according to the fluorescence anisotropy of the hydrophobic polyene 1,6-diphenylhexatriene and of the fluorescence emission maxima of the amphiphilic probe 6-dodecanoyl-2-dimethylaminonaphthalene. Binding parameters were obtained from the fluorescence anisotropy measurements in combination with our previous determinations by titration calorimetry (Nuscher, B., Kamp, F., Mehnert, T., Odoy, S., Haass, C., Kahle, P. J., and Beyer, K. (2004) J. Biol. Chem. 279, 21966-21975). We also show that alpha-synuclein interacts with vesicle membranes containing sphingomyelin and cholesterol. We propose that the protein is capable of annealing defects in curved vesicle membranes, which may prevent synaptic vesicles from premature fusion."

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The Niemann-Pick C1 protein in recycling endosomes of presynaptic nerve terminals
Karten B, Campenot RB, Vance DE, Vance JE
Canadian Institutes for Health Research Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
J Lipid Res. (March 2006) 47(3): 504-14
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Abstract: "Niemann-Pick type C (NPC) disease is a fatal, neurodegenerative disorder caused in 95% of cases by loss of function of NPC1, a ubiquitous endosomal transmembrane protein. A biochemical hallmark of NPC deficiency is cholesterol accumulation in the endocytic pathway. Although cholesterol trafficking defects are observed in all cell types, neurons are the most vulnerable to NPC1 deficiency, suggesting a specialized function for NPC1 in neurons. We investigated the subcellular localization of NPC1 in neurons to gain insight into the mechanism of action of NPC1 in neuronal metabolism. We show that NPC1 is abundant in axons of sympathetic neurons and is present in recycling endosomes in presynaptic nerve terminals. NPC1 deficiency causes morphological and biochemical changes in the presynaptic nerve terminal. Synaptic vesicles from Npc1(-/-) mice have normal cholesterol content but altered protein composition. We propose that NPC1 plays a previously unrecognized role in the presynaptic nerve terminal and that NPC1 deficiency at this site might contribute to the progressive neurological impairment in NPC disease."

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Brain cholesterol turnover required for geranylgeraniol production and learning in mice
Kotti TJ, Ramirez DM, Pfeiffer BE, Huber KM, Russell DW
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Proc Natl Acad Sci USA. (7 March 2006) 103(10): 3869-74 (ePub 27 Feb 2006)
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Abstract: "The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24-hydroxylase on LTP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning."

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Cholesterol and synaptic transmitter release at crayfish neuromuscular junctions
Zamir O, Charlton MP
Physiology Department, University of Toronto, 1 King's College Circle, Room 3308, Toronto, Ontario, Canada M5S1A8
J Physiol. (15 Feb 2006) 571(Pt 1): 83-99
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Abstract: "During exocytosis of synaptic transmitters, the fusion of highly curved synaptic vesicle membranes with the relatively planar cell membrane requires the coordinated action of several proteins. The role of membrane lipids in the regulation of transmitter release is less well understood. Since it helps to control membrane fluidity, alteration of cholesterol content may alter the fusibility of membranes as well as the function of membrane proteins. We assayed the importance of cholesterol in transmitter release at crayfish neuromuscular junctions where action potentials can be measured in the preterminal axon. Methyl-beta-cyclodextrin (MbetaCD) depleted axons of cholesterol, as shown by reduced filipin labelling, and cholesterol was replenished by cholesterol-MbetaCD complex (Ch-MbetaCD). MbetaCD blocked evoked synaptic transmission. The lack of postsynaptic effects of MbetaCD on the time course and amplitude of spontaneous postsynaptic potentials or on muscle resting potential allowed us to focus on presynaptic mechanisms. Intracellular presynaptic axon recordings and focal extracellular recordings at individual boutons showed that failure of transmitter release was correlated with presynaptic hyperpolarization and failure of action potential propagation. All of these effects were reversed when cholesterol was replenished with Ch-MbetaCD. However, focal depolarization of presynaptic boutons and administration of a Ca2+ ionophore both triggered transmitter release after cholesterol depletion. Therefore, both presynaptic Ca2+ channels and Ca2+-dependent exocytosis functioned after cholesterol depletion. The frequency of spontaneous quantal transmitter release was increased by MbetaCD but recovered when cholesterol was reintroduced. The increase in spontaneous release was not through a calcium-dependent mechanism because it persisted with intense intracellular calcium chelation. In conclusion, cholesterol levels in the presynaptic membrane modulate several key properties of synaptic transmitter release."

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Lipid rafts are involved in C95 (4,8) agrin fragment-induced acetylcholine receptor clustering
Campagna JA, Fallon J
Department of Anesthesia, Longnecker Anesthesia Research Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA
Neuroscience (2006) 138(1): 123-32 (ePpub 27 Dec 2005)
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Abstract: "During development of the neuromuscular junction, high densities of acetylcholine receptors accumulate beneath the overlying nerve terminal. A defining feature of mature synapses is the sharp demarcation of acetylcholine receptor density, which is approximately 1000-fold higher in the postsynaptic as compared with the contiguous extrasynaptic muscle membrane. These high densities of receptors accumulate by at least four mechanisms, re-distribution of existing surface receptors, local synthesis of new receptors, decreased turnover of synaptic receptors, and limitation of diffusion of sub-neural, aggregated receptors. The limitation of receptor diffusion within the membrane is likely in part due to the anchoring of acetylcholine receptor complexes to components of the cytoskeleton. Here we have tested the idea that lipid rafts--mobile, cholesterol enriched microdomains within the lipid bilayer--are another mechanism by which acetylcholine receptors are clustered in the postsynaptic apparatus. Using mouse C2C12 cells, a muscle cell line, we show that a carboxy terminal 95 amino acid fragment [C95 (4,8)] of the extracellular matrix molecule agrin that is essential for nerve-induced postsynaptic differentiation, promotes the redistribution of acetylcholine receptors into lipid rafts. Disruption of lipid rafts before agrin treatment largely inhibits de novo agrin-induced acetylcholine receptor clustering. Moreover, mature acetylcholine receptor clusters are destabilized if lipid rafts are disrupted. These results show that lipid rafts are important in both the initial clustering and later stabilization of agrin-induced acetylcholine receptor clusters and also suggest that lipid rafts may contribute to the postsynaptic localization of acetylcholine receptors in vivo."

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Amyloid precursor protein expression in the rat hippocampal dentate gyrus modulates during memory consolidation
Conboy L, Murphy KJ, Regan CM
Applied Neurotherapeutics Research Group, Department of Pharmacology, Conway Institute, University College Dublin, Belfield, Dublin, Ireland
J Neurochem (Dec 2005) 95(6):1677-88
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Abstract: "Despite advances in our understanding of the basic biology of amyloid precursor protein (APP), the normal physiological function(s) of APP in learning and memory remains unclear. Here we show increased APP degradation in the hippocampus to be associated with the consolidation of a passive avoidance response. Neurone-specific APP695 expression became transiently reduced 2-4 h post-training through association with endosomal adaptin proteins and enhanced internalization. By contrast, internalization of glial-associated APP containing a Kunitz protease inhibitor-like domain (APP-KPI) was dependent on the low-density lipoprotein receptor-related protein (LRP). In addition, LRP expression and association with apolipoprotein E increased in the 2-4 h post-training period. The LRP antagonist receptor-associated protein prevented the APP-KPI internalization and LRP-apolipoprotein E association and this resulted in amnesia. Degradation of APP695 and APP-KPI did not appear to be related to alpha-secretase activity, as no learning-associated increase of secreted APP was observed in the CSF. Moreover, as internalization of APP isoforms was observed only in dentate gyrus, it probably relates to the learning-associated restructuring of the perforant path terminals. Memory-associated APP processing in both neuronal and glial compartments points to a role for glial unsheathing of synaptic connections, an event required for the synaptic restructuring that accompanies memory consolidation. These observations may have a direct relevance to understanding the pathophysiology of Alzheimer's disease as beta/gamma-secretase-derived beta-amyloid is formed following internalization of cell surface APP into the endosomal compartment."

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Exercise-induced changes in cardiac gene expression and its relation to spatial maze performance
Schweitzer NB, Alessio HM, Berry SD, Roeske K, Hagerman AE
Department of Zoology, Miami University, Oxford, OH 45056, USA
Neurochem Int. (January 2006) 48(1): 9-16
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Abstract: "Cognitive performance is sensitive to both neural and non-neural changes induced by physical activity and inactivity. This study investigated whether access to physical activity outside a standard laboratory animal cage affected cognitive performance as measured by navigation of a spatial maze. It also examined gene expression in heart tissue for genes associated with cardiovascular function given recent reports of cognitive impairment associated with hyperlipidemia. Furthermore, we measured expression of neural-regulatory genes typically expressed in brain, but also found in cardiac tissue. Male Sprague-Dawley rats (n = 72) were separated into three groups having different access to physical activity: none outside a standard cage, twice-weekly physical activity, and every other day exercise on a running wheel. Compared with a sedentary group, spatial maze performance was enhanced in animals that had access to physical activity, either twice-weekly in a large box or every other day on a running wheel. Both the cardiovascular and neural-related genes expressed in the heart were distinguished by access to physical activity. Several genes that are associated with heart rate, cholesterol biosynthesis, blood pressure, and cell adhesion regulation, including GJA1, FDFT1, EDN1, and CD36, differed in animals based on access to physical activity. Neural-related genes expressed in cardiac tissue associated with neurite outgrowth, neuroplasticity, and neurogenesis including RTN4, HOMER2, ACTB, NCDN, KIF5B, and HMGB2, were expressed differently among the three groups. Significant shifts in ten cardiovascular and neural-related gene expressions in cardiac tissue were associated with physical activity and may have influenced learning and performance on a spatial maze."

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Cholesterol, copper and Abeta in controls, MCI, AD and the AD cholesterol-lowering treatment trial (ADCLT)
Sparks DL, Petanceska S, Sabbagh M, Connor D, Soares H, Adler C, Lopez J, Ziolkowski C, Lochhead J, Browne P
Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ, USA
Curr Alzheimer Res. (Dec 2005) 2(5): 527-39
[PubMed] [Related article 1] [Authors contact]
 

Abstract: "Cholesterol clearly plays an influential role in promoting the production of amyloid beta (Abeta) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N = 32) compared to placebo (N = 31). We assessed the circulating levels of Abeta(1-40), Abeta(1-42), ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Abeta levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Abeta(1-40) occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Abeta(1-40) levels were decreased in AD compared to MCI. Levels of Abeta(1-42) were not significantly different between the groups. The slight gradual increase in circulating Abeta(1-40) and Abeta(1-42) levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Abeta(1-40) levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Abeta or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration."

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