Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer's Disease but is not causative

Bennett, C. Ray; Crawford, Fiona; Osborne, Aaron; Díaz, Patricia Jaramillo; Hoyne, Jonathan; Lopez, Robert; Roques, P; Duara, Ranjan; Rossor, Martin N.; Mullan, Michael

doi:10.1002/ajmg.1320600102

Cited by 65 publications

(41 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This earlier age of onset is a consistent finding associated with apoE ⑀4/4 (Corder et al, 1993;Soininen, 1995). Other studies, furthermore, have reported on a more rapid progression of the disease in these patients (Bennett et al, 1995). These findings implicate that patients with apoE ⑀4 alleles might reach more advanced stages of the disease at a younger age than patients without ⑀4.…”

Section: Apoe Genotype and Stage Dependency Of Reparative Capacitysupporting

confidence: 81%

“…It has been shown recently that the ⑀4 allele is a major risk factor for late-onset familial AD and probably also for sporadic AD (Corder et al, 1993;Mayeux et al, 1993;Poirier et al, 1993b;Rebeck et al, 1993;Saunders et al, 1993;Strittmatter et al, 1993a). Moreover, AD patients with ⑀4 alleles usually show an earlier age of onset (Corder et al, 1993;Basun et al, 1995;Locke et al, 1995) and a more rapid progression of the disease (Bennett et al, 1995), suggesting a causal link between apoE polymorphism and the development of AD (for review, see Roses et al, 1994).…”

Section: Abstract: Alzheimer's Disease; Apolipoprotein E; Degeneratimentioning

confidence: 99%

See 1 more Smart Citation

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Arendt¹,

Schindler²,

Brückner³

et al. 1997

J. Neurosci.

309

174

View full text Add to dashboard Cite

A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer's disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system.In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer's disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE ⑀4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE ⑀4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE ⑀4 allele was very weak in the presence of one ⑀4 allele and completely lost in patients homozygous for the ⑀4 allele.The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer's disease carrying the apoE ⑀4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.

show abstract

Section: Apoe Genotype and Stage Dependency Of Reparative Capacitysupporting

confidence: 81%

Section: Abstract: Alzheimer's Disease; Apolipoprotein E; Degeneratimentioning

confidence: 99%

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Arendt¹,

Schindler²,

Brückner³

et al. 1997

J. Neurosci.

309

174

View full text Add to dashboard Cite

show abstract

“…mRNA for Srebf1 (sterol regulatory element binding factor 1), implicated in lipogenic gene expression (33), was down-regulated in ␥3 R225Q mutant mice, whereas mRNA encoding for Ppargc1a (peroxisome proliferative-activated receptor, ␥ coactivator 1 ␣), known to increase the expression of both nuclear and mitochondrial-encoded genes of oxidative metabolism (34), was up-regulated. Additionally, a key gene integral to free fatty acid uptake (Cd36 (35)), as well as genes involved in use of fat-derived energy (3-oxoacid-CoA transferase 1, Oxct1, EC 2.8.3.5 and carboxylesterase 3, Ces3, EC 3.1.1.1) were up-regulated in TgPrkag3 225Q mice.…”

Section: ␥3-containing Ampk Heterotrimers Regulate Lipid Metabolism Gmentioning

confidence: 99%

Opposite Transcriptional Regulation in Skeletal Muscle of AMP-activated Protein Kinase γ3 R225Q Transgenic Versus Knock-out Mice

Nilsson¹,

Long

Martinsson³

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

AMP-activated protein kinase (AMPK) is an evolutionarily conserved heterotrimer important for metabolic sensing in all eukaryotes. The muscle-specific isoform of the regulatory ␥-subunit of the kinase, AMPK ␥3, has an important role in glucose uptake, glycogen synthesis, and fat oxidation in white skeletal muscle, as previously demonstrated by physiological characterization of AMPK ␥3 mutant (R225Q) transgenic (TgPrkag3 225Q ) and ␥3 knock-out (Prkag3 ؊/؊ ) mice. We determined AMPK ␥3-dependent regulation of gene expression by analyzing global transcription profiles in glycolytic skeletal muscle from ␥3 mutant transgenic and knock-out mice using oligonucleotide microarray technology. Evidence is provided for coordinated and reciprocal regulation of multiple key components in glucose and fat metabolism, as well as skeletal muscle ergogenics in TgPrkag3 225Q and Prkag3 ؊/؊ mice. The differential gene expression profile was consistent with the physiological differences between the models, providing a molecular mechanism for the observed phenotype. The striking pattern of opposing transcriptional changes between TgPrkag3 225Q and Prkag3 ؊/؊ mice identifies differentially expressed targets being truly regulated by AMPK and is consistent with the view that R225Q is an activating mutation, in terms of its downstream effects. Additionally, we identified a wide array of novel targets and regulatory pathways for AMPK in skeletal muscle.AMP-activated protein kinase (AMPK) 2 is a critical regulator of carbohydrate and fat metabolism in eukaryotic cells (reviewed in Refs. 1 and 2). AMPK is a heterotrimer that consists of ␣-, ␤-, and ␥-subunits, all of which are required for its activity. The catalytic ␣-subunit contains a conventional serine/threonine protein kinase domain, and phosphorylation of Thr-172 residue within the activation loop of the ␣-subunit by upstream kinases is essential for the activity of the heterotrimer (3-6). Once phosphorylated at Thr-172, AMPK can be further activated by allosteric binding of AMP to the evolutionary conserved cystathionine ␤-synthase domains in the regulatory ␥-subunit (7). The AMPK ␤-subunit acts as a scaffold for binding of the ␣-and ␥-subunits (8). The ␤-subunit also contains a glycogen-binding domain, and recent findings provide evidence that this motif is involved in targeting the AMPK complex to cellular glycogen stores (9, 10). The mammalian genome contains seven AMPK genes encoding for two ␣-, two ␤-, and three ␥-isoforms. Thus, there are 12 possible combinations of heterotrimeric AMPK, and the physiological function of the AMPK holoenzyme depends on the particular isoforms present in the complex.We have provided evidence that AMPK ␥3 is the predominant ␥-isoform expressed in glycolytic (white, fast-twitch type II) skeletal muscle (11). In contrast, it is expressed at low levels in oxidative (red, slowtwitch type I) skeletal muscle and is undetectable in brain, liver, heart, or white adipose tissue (11). Thus, the AMPK ␥3-subunit is the only isoform exhibiting tissue-specific ...

show abstract

“…A great deal of interest has been generated concerning the role of the ApoE as a risk factor for AD and an association between late-onset AD and the ApoE locus on chromosome 19 (Roses, 1994;Bennett, 1995;Cacabelos, 1996;Cacabelos et al, 1996), has been recently observed. Apolipoprotein E is a secretory glycoprotein and the three common allelic isoforms of this protein (ApoE 2, ApoE 3, and ApoE 4) are associated with distinct patterns of lipoprotein metabolism and variable risks for coronary artery disease (Tiret, 1994), raising the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain.…”

Section: Introductionmentioning

confidence: 99%

Microglial activation induced by factor(s) contained in sera from Alzheimer-related ApoE genotypes

1998

View full text Add to dashboard Cite

Several factors that increase the likelihood of developing Alzheimer's disease (AD) have already been identified. A correct evaluation of these may contribute to a better understanding of the etiology of the disease. The risk of developing AD definitely increases with (a) age, (b) head injuries, (c) family history of AD or Down syndrome, (d) sex (higher prevalence of AD in women), (e) vascular disease, (f) exposure to environmental toxins, (g) infectious processes, or (h) changes in immune function, and recent advances in molecular genetics have suggested that genetic predisposition (i) can be considered one of the most important risk factors in the development of AD. A significant increase in the number of amyloid plaques in AD patients with an apolipoprotein E4 (ApoE) allele has been observed and the results of several genetic studies indicate that the etiology of this neurodegenerative disease is associated with the presence of the allele E4 of ApoE. A potential source of damage in the AD brain is an altered response triggered by microglial activation, which is associated with amyloid plaques. It has become evident that a dysregulation of cytokine release appears within lesions of many types of brain disorders including infection, trauma, stroke, and neurodegenerative diseases. Many studies have shown that microglia secrete both cytokines and cytotoxins and since reactive microglia appears in nearly every type of brain damage, it is likely that their secreted products ultimately help to determine the rate of damaged brain tissue. In this study, in vitro cell cultures were established to investigate the effect of different concentrations of human sera (2.5% and 10%) with specific ApoE genotypes from Alzheimer's and non-Alzheimer's subjects on ameboid and flat microglial cells obtained from neonatal rat hippocampi. Results show that a modulation in the proliferation and activation of microglial cells was obtained and that AD sera, mainly in the ApoE 3/4 and 4/4 genotype contain factor(s) which are able to induce morphological changes, as measured by an increase in the ameboid cell type. In addition, major histocompatibility complex (MHC) class II antigen expression, as measured by flow cytometric analysis, and interleukin-1beta (IL-1beta) release as measured by enzyme linked immunoadsorbent assay (ELISA), in comparison with control groups and lipopolysaccharide (LPS)-treated cells, clearly demonstrate a direct effect of ApoE 3/4 and 4/4 and/or an indirect effect mediated by the release of IL-1beta on microglia activation. These results strongly suggest that primary in vitro microglial cell cultures can be used as a screening model to test human sera as well as the effect of new potential drugs aimed at down-regulating microglia activation.

show abstract

Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer's Disease but is not causative

Cited by 65 publications

References 18 publications

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Opposite Transcriptional Regulation in Skeletal Muscle of AMP-activated Protein Kinase γ3 R225Q Transgenic Versus Knock-out Mice

Microglial activation induced by factor(s) contained in sera from Alzheimer-related ApoE genotypes

Contact Info

Product

Resources

About