Association at LRP gene locus with sporadic late-onset Alzheimer's disease

Lambert, Jean‐Charles; Vrièze, Fabienne Wavrant‐De; Amouyel, Philippe; Chartier-Harlin, Marie-Christine

doi:10.1016/s0140-6736(05)78749-3

Cited by 92 publications

(67 citation statements)

References 5 publications

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“…185) Whereas it is strongly suggested that ligands for LRP1, such as APP, a2-macroglobulin and apo E, are genetically linked to the increased risk and/or age of onset of AD, 135,186,187) any genetic association of LRP1 with AD remains unclear. [188][189][190][191][192] The scavenger receptor class B type I (SR-BI) has been characterized as an HDL receptor and is expressed in microglia and astrocytes. 193,194) Reduction of SR-BI in a mouse model of AD (J20) induced a deterioration in learning and memory and promoted cerebral amyloid angiopathy as well as the deposition of fibrillar Ab in the hippocampus.…”

Section: Lipid Metabolism and Admentioning

confidence: 99%

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFunctions of the central nervous system (CNS) are performed mainly by neurons and glia-primarily astrocytes, microglia and oligodendrocytes. It has been thought for a long time that glia only passively support neurons, but we now know that glia actively attend to assist in neuronal functions like synaptogenesis and neurotransmission. 1) Although it was believed that ca. 90% of the cells in the brain are glia and the rest of cells are neurons, Azevedo et al. recently reported that the numbers of neurons and non-neuronal cells (glia) are close to equal in human adult brain.2) Brain is the most cholesterol-rich organ in the body, and cholesterol metabolism in the CNS is tightly regulated between neurons and glia. [3][4][5][6][7] Imbalances in the metabolism of lipids, especially cholesterol, are closely linked to the development of several neurodegenerative disorders such as Alzheimer's disease, 8,9) Niemann-Pick type C disease 10) and Smith-Lemli Opitz syndrome. 11,12) In this review the regulation of lipid metabolism and the roles of glial lipoproteins in the CNS will be discussed. LIPID HOMEOSTASIS IN THE CNSThe system of lipid metabolism and transport in the CNS is different from that in peripheral tissues because the CNS is segregated from the peripheral circulation by the blood-brain barrier (BBB).13) Although lipoprotein particles can cross the BBB in vivo in Drosophila, which has a functional BBB like that in vertebrates, 14) lipoproteins in the mouse, rat and human do not cross the BBB. Consequently, since labeled cholesterol peripherally administrated was not found in the CNS of mammals, 15,16) cholesterol in the CNS is derived from de novo synthesis inside of the CNS. Furthermore, in the plasma of subjects who had liver transplantation the genotype of apolipoprotein (apo) E was that of the donor, whereas the subjects retained the own apo E genotype in the cerebrospinal fluid (CSF).17) Moreover, lipoproteins in the CNS consist of only high density lipoprotein (HDL)-like particles in contrast to the circulation which contains very low density lipoproteins (VLDL), low density lipoproteins (LDL) and HDL. It is known that the HDL-like particles in the CNS are secreted from glia (glial lipoproteins), mainly astrocytes and microglia, under normal conditions, [18][19][20] however lipoproteins can be secreted from neurons in vitro 21,22) and in vivo 23) under some specific conditions. Unesterified cholesterol is the major sterol in the adult brain, and small amounts of desmosterol and cholesteryl ester are also present. The majority (70-80%) of cholesterol in the adult brain is in myelin formed by oligodendrocytes. 24)Thus, the activity of cholesterol synthesis in the CNS is the highest during the myelinogenesis. After myelination, cholesterol synthesis continues at very low level in the CNS, and occurs mainly in astrocytes. 5,13,24) Neurons do not efficiently synthesize cholesterol and rely on external source of cholesterol from astrocytes, 25) so that neurons take up cholesterol as lipoproteins via ...

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Section: Lipid Metabolism and Admentioning

confidence: 99%

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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“…In view of the preceding observations, we next asked whether the correlation between LRP levels and AD susceptibility can be confirmed by a different analysis. The recently reported under-representation of the LRP exon 3 (C766T) polymorphism in late-onset AD has been demonstrated in five different populations (8)(9)(10)(11)(12), although the putative causative mutation/polymorphism in linkage disequilibrium with the C766T polymorphism remains to be identified. Because our current results demonstrated that the level of LRP in the brain is correlated with disease onset, we examined whether a manifestation of the C766T polymorphism is also reflected in LRP expression.…”

Section: Lrp Mediates the Clearance Of Secreted Aβ Without Altering Amentioning

confidence: 99%

Modulation of amyloid β-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor–related protein pathway

Kang¹,

Pietrzik²,

Baum³

et al. 2000

J. Clin. Invest.

336

284

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“…APP also controls aquaporin 1 gene expression by epigenetic control mechanism (22). The Swedish mutation of APP, replacement of Lys-595 and Met-596 with Asp and Lys respectively, enhances early-onset and propagation of AD, and leads to the cognitive impairments associated with AD (23).…”

Section: Introductionmentioning

confidence: 99%

Swedish mutation within amyloid precursor protein modulates global gene expression towards the pathogenesis of Alzheimer's disease

Shin¹,

Yu²,

Yu³

et al. 2010

BMB Reports

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The Swedish mutation (K595N/M596L) of amyloid precursor protein (APP-swe) has been known to increase abnormal cleavage of cellular APP by Beta-secretase (BACE), which causes tau protein hyperphosphorylation and early-onset Alzheimer's disease (AD). Here, we analyzed the effect of APP-swe in global gene expression using deep transcriptome sequencing technique. We found 283 genes were down-regulated and 348 genes were up-regulated in APP-swe expressing H4-swe cells compared to H4 wild-type cells from a total of approximately 74 million reads of 38 base pairs from each transcriptome. Two independent mechanisms such as kinase and phosphatase signaling cascades leading hyperphosphorylation of tau protein were regulated by the expression of APP-swe. Expressions of catalytic subunit as well as several regulatory subunits of protein phosphatases 2A were decreased. In contrast, expressions of tau-phosphorylating glycogen synthase kinase 3β (GSK-3β), cyclin dependent kinase 5 (CDK5), and cAMP-dependent protein kinase A (PKA) catalytic subunit were increased. Moreover, the expression of AD-related Aquaporin 1 and presenilin 2 expression was regulated by APP-swe. Taken

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Association at LRP gene locus with sporadic late-onset Alzheimer's disease

Cited by 92 publications

References 5 publications

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Modulation of amyloid β-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor–related protein pathway

Swedish mutation within amyloid precursor protein modulates global gene expression towards the pathogenesis of Alzheimer's disease

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