Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population

Lendon, Corinne; Talbot, Chris J.; Craddock, Nick; Han, Sang Woo; Wragg, Michelle; Morris, John C.; Goate, Alison M.

doi:10.1016/s0304-3940(97)13381-x

Cited by 133 publications

(71 citation statements)

References 16 publications

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“…LRP and the VLDLR were studied as candidate genes to AD and were inconsistently associated with AD. [20][21][22]44 Herein we found that the þ 766C4T polymorphism of exon 3 of the LRP gene was not associated, when analysed alone, with an increased risk of AD (OR 1.2 (95% CI, 0.9-1.8), P ¼ 0.24) although a metaanalysis of all previous works indicated a modest association between the CC genotype and AD (OR 1.35 (95% CI, 1.1-1.7), P ¼ 0.01). 45 We also found a trend for association between the A to G substitution of MAPK8IP1 and an increased risk of AD when the two studies were pooled together, and the association in early-onset AD should be only a chance result.…”

Section: Discussionmentioning

confidence: 99%

“…As an example, LRP and ApoER2 interact with IB1/ JIP1 13,14 . In human, polymorphisms within the LRP and FE65 genes were described as risk factors to Alzheimer's disease (AD) [19][20][21][22][23][24] . Since IB1/JIP-1 is related to FE65 and interacts with several cellular partners that are critical for neuronal cell function and/or have been associated with human AD, we hypothesized that abnormal expression or function of the IB1/JIP-1 protein could contribute to the pathogenesis of neurodegenerative diseases such as AD.…”

Section: Introductionmentioning

confidence: 99%

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Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

et al. 2003

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Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/ JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the lowdensity lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a À499A4G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the À499A4G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the þ 766C4T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A4G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

et al. 2003

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“…Recent data also show that LRP and TFPI immunoreactivity associates with A␤-containing plaques in the AD brain (3,29). Finally, two recent studies suggest a genetic association between certain polymorphisms in LRP and the risk of developing AD (30,31). Taken together, these findings suggest that LRP could play a role in AD pathogenesis by 1) modifying A␤ uptake and clearance through A␤ interactions with LRP ligands such as ␣ 2 M* and apoE/lipoprotein or 2) direct effects of ligands on cells.…”

mentioning

confidence: 97%

Nerve Growth Factor Induces Rapid Increases in Functional Cell Surface Low Density Lipoprotein Receptor-related Protein

Bu¹,

Sun²,

Schwartz³

et al. 1998

Journal of Biological Chemistry

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The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that binds multiple ligands and is highly expressed in neurons. Several LRP ligands, including apolipoprotein E/lipoproteins and amyloid precursor protein, have been shown to participate either in Alzheimer's disease pathogenesis or pathology. However, factors that regulate LRP expression in neurons are unknown. In the current study, we analyzed the effects of nerve growth factor (NGF) treatment on LRP expression, distribution, and function within neurons in two neuronal cell lines. Our results show that NGF induces a rapid increase of cell surface LRP expression in a central nervous system-derived neuronal cell line, GT1-1 Trk, which was seen within 10 min and reached a maximum at about 1 h of NGF treatment. This increase of cell surface LRP expression is concomitant with an increase in the endocytic activity of LRP as measured via ligand uptake and degradation assays. We also found that the cytoplasmic tail of LRP is phosphorylated and that NGF rapidly increases the amount of phosphorylation. Furthermore, we detected a significant increase of LRP expression at the messenger RNA level following 24 h of NGF treatment. Both rapid and long term induction of LRP expression were also detected in peripheral nervous system-derived PC12 cells following NGF treatment. Taken together, our results demonstrate that NGF regulates LRP expression in neuronal cells.The low density lipoprotein receptor-related protein (LRP) 1 is a large multiligand endocytic receptor expressed abundantly in liver and brain (1). In brain, it is expressed by most if not all neurons and some glial cells (2-4). LRP is the largest endocytic receptor identified to date (ϳ600 kDa; see Ref. 5), synthesized as a single polypeptide chain and cleaved in the trans-Golgi into two subunits (6, 7). A 39-kDa receptor-associated protein (RAP) is a unique LRP ligand antagonist (8, 9), which can also bind and antagonize ligand binding to other low density lipoprotein receptor family members (10 -12).While LRP has been shown to have over 10 ligands (1), four of these (apolipoprotein E (apoE)/lipoproteins, ␣ 2 -macroglobulin (␣ 2 M*) complexed with or without the amyloid peptide (A␤), tissue factor pathway inhibitor (TFPI), and ␤-amyloid precursor protein (APP)) have been shown to participate either in Alzheimer's disease pathogenesis or pathology. For example, the ⑀4 allele of apoE is a major risk factor for late onset AD (13-15). While the mechanism for this association is not yet clear, apoE has been found to associate with both A␤ and Tau both in vivo and in vitro (16 -19), and recent data suggest that apoE/lipoprotein uptake through neuronal LRP can modify toxic effects of A␤ (20). In addition, studies have shown that isoforms of apoE when conjugated to lipoproteins can differentially influence neurite outgrowth via cell surface LRP (21-24). ␣ 2 M is one of several constituents of A␤-containing plaques in AD brain (25,26). We and others have recently found that ␣ 2 M compl...

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“…The low-density lipoprotein (LDL) receptor-related protein (LRP) has been genetically linked to AD (3,4) and has been shown to influence A␤ metabolism in vitro (5)(6)(7)(8)(9)(10)(11)(12). LRP is an Ϸ600-kDa cell-surface endocytic receptor member of the LDL receptor family (13).…”

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confidence: 99%

Increased soluble amyloid-β peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein

Zerbinatti

Wozniak²,

Cirrito

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

125

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Amyloid-␤ peptide (A␤) is central to the pathogenesis of Alzheimer's disease, and the low-density lipoprotein receptor-related protein (LRP) has been shown to alter A␤ metabolism in vitro. Here, we show that overexpression of a functional LRP minireceptor in the brain of PDAPP mice results in age-dependent increase of soluble brain A␤, with no changes in A␤ plaque burden. Importantly, soluble brain A␤ was found to be primarily in the form of monomers͞dimers and to be highly correlated with deficits in spatial learning and memory. These results provide in vivo evidence that LRP may contribute to memory deficits typical of Alzheimer's disease by modulating the pool of small soluble forms of A␤.A lzheimer's disease (AD) is characterized by cognitive impairment and neuronal loss that have been primarily linked to the accumulation of extracellular neuritic plaques and intracellular neurofibrillary tangles in the brain (1). The major component of neuritic plaques is amyloid-␤ peptide (A␤), which is derived from the cleavage of amyloid precursor protein (APP). Accumulation of fibrillar aggregates of A␤ in the brain parenchyma, caused by A␤ overproduction, impaired clearance, or both, is the basis for the amyloid cascade hypothesis long proposed to explain the etiology of AD (2).The low-density lipoprotein (LDL) receptor-related protein (LRP) has been genetically linked to AD (3, 4) and has been shown to influence A␤ metabolism in vitro (5-12). LRP is an Ϸ600-kDa cell-surface endocytic receptor member of the LDL receptor family (13). LRP is highly expressed in the brain and is considered the major neuronal receptor for apolipoprotein E (apoE) and ␣ 2 -macroglobulin (␣ 2 M), also implicated in the pathogenesis of AD by both biochemical and genetic evidence (14).A putative role for LRP in AD is supported by in vitro studies showing that apoE and ␣ 2 M can form stable complexes with A␤ and promote its clearance via cell-surface LRP (5-10). Furthermore, LRP appears to influence APP endocytic trafficking and cellular distribution such that processing to A␤ and its extracellular release are enhanced (11,12). To assess the effect of LRP on A␤ deposition in vivo, we generated transgenic (TG) mice that overexpress a functional minireceptor of LRP in the brain. We bred LRP TG mice to PDAPP TG mice, an animal model that develops amyloid plaques similar to those seen in AD (15). Although brain A␤ plaque burden was not significantly altered by the overexpression of LRP, double TG mice showed an age-dependent increase of soluble brain A␤ levels when compared to littermate mice overexpressing APP alone. The A␤ levels in this soluble brain extracts, which we found to be mostly A␤ monomers and dimers, were highly correlated with deficits in spatial learning and memory. These data provide strong evidence that, in addition to A␤ plaques, small soluble forms of A␤ appear to impair neuronal function and contribute to memory deficits in vivo. Materials and MethodsAnimals and Tissue Preparation. mLRP2 TG mice were generated in a B6͞C3H backgr...

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Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population

Cited by 133 publications

References 16 publications

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

Nerve Growth Factor Induces Rapid Increases in Functional Cell Surface Low Density Lipoprotein Receptor-related Protein

Increased soluble amyloid-β peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein

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