ApoE4 correlation with MPB -- is there any increased odds of having MPB if you carry it?

Anxious1 wrote:i dont know, but ive just studied the apoE genes at university 3 yr genetics and apoE4 has increased risk of alzheimers and cholesterol, where do u get increased risk of mpb from?

has it been proven or is it just anecdotal?

Altered immune responses in apolipoprotein E-deficient mice

D. T. Laskowitz1,*,
D. M. Lee*,
D. Schmechel* and
H. F. Staats*†

+ Author Affiliations

*Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710
†Department of Immunology, Duke University Medical Center, Durham, NC 27710

1 To whom correspondence should be addressed.


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Abstract

Apolipoprotein E (apoE) is a 34 kDa glycosylated protein with multiple biological properties. In addition to its role in cholesterol transport, apoE has in vitro immunomodulatory properties. Recent data suggest that these immunomodulatory effects of apoE may be biologically relevant, and apoE-deficient mice have altered immune responses after bacterial inoculation and increased susceptibility to endotoxemia induced by lipopolysaccharide (LPS). To better understand the mechanism by which apoE-modulates immune responses, we tested the role of human apoE isoforms in assays of human T cell proliferation, and analyzed the immune responses of apoE-deficient mice. Both the E3 and E4 isoforms of apoE induced similar suppression of human lymphocyte function in assays of T cell proliferation, including mitogenic responses to phytohaemagglutin (PHA), stimulation of the T cell receptor with αCD3, and antigen-specific response to tetanus toxoid. ApoE-deficient mice showed no quantitative differences in thymic, splenic, or bone marrow lymphocyte populations, nor were there in vitro abnormalities in splenocyte proliferation after stimulation with αCD3 to suggest an inherent T cell defect in apoE-deficient mice. ApoE deficient animals, however, had significantly higher levels of antigen-specific IgM after immunization with tetanus toxoid, and impaired delayed type hypersensitivity responses as compared to control C57-BL/6 mice. These results support a growing body of evidence demonstrating an interplay between lipid metabolism and immune responses, and suggest that apoE plays a biologically relevant role in regulating humoral and cell-mediated immunity.

The reasons for the differences in outcome of infection are largely unknown, but genetic factors presumably play a major role. We have found that polymorphisms in the gene encoding the protein apolipoprotein E (APOE) determine the consequences of infection with several diverse pathogens. This gene has three major alleles, APOE-alt epsilon2, alt epsilon3 and alt epsilon4, which correspond to three main protein isoforms, apoE2, 3, and 4. The protein is a multipurpose molecule with roles in lipid transport, tissue repair and the immune system.1 We have identified a new function for apoE – control of pathogens. First, the APOE-alt epsilon4 and the APOE-alt epsilon2 alleles are, respectively, risk factors for herpes labialis and herpes simplex encephalitis, diseases caused by herpes simplex virus type 1 (HSV1).2, 3, 4 Second, the APOE-alt epsilon4 allele is strongly protective against hepatitis C virus-induced liver damage,5 and the APOE-alt epsilon2alt epsilon2 genotype is associated with earlier infection with the malaria parasite.6 Also, we have discovered that a derivative of apoE has anti-infective properties.7 These findings all stem from our initial discovery that APOE-alt epsilon4 and HSV1 (in brain) together confer a strong risk of Alzheimer's disease.2, 3

The common factor linking apoE and these pathogens is their usage of the same molecules to attach to and/or to enter cells, namely, heparan sulphate proteoglycans (HSPG) and members of the low-density lipoprotein receptor (LDLR) family, respectively. ApoE might control infection by competing with the pathogen for binding to these molecules.2 If the extent of binding is isoform-specific, APOE will determine extent of competition, and hence of entry of the pathogen into cells and its subsequent spread, damage and disease. Dependence of binding affinities of the apoE isoforms on cell type could result in a specific allele protecting in one disease but conferring a risk in another.

Infiltration of the brain by pathogens causes Alzheimer’s disease
R.F. Itzhaki a,∗, M.A. Wozniak a, D.M. Appelt b, B.J. Balin c
a Molecular Neurobiology Laboratory, Department of Optometry and Neuroscience, University of Manchester
Institute of Science and Technology (UMIST), Manchester M60 1QD, UK
b Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 19131, USA
c Department of Pathology/Microbiology and Immunology, Philadelphia College of Osteopathic Medicine,
4170 City Avenue, Philadelphia, PA 19131, USA
Received 10 October 2003; received in revised form 5 December 2003; accepted 8 December 2003
Abstract
Despite very numerous studies on Alzheimer’s disease (AD), especially on amyloid plaques and neurofibrillary tangles, little information
has been obtained thus on the causes of the disease. Evidence is described here that implicates firstly herpes simplex virus type 1 (HSV1)
as a strong risk factor when it is present in brain of carriers of the type 4 allele of the gene for apolipoprotein E (APOE-ε4). Indirect support
comes from studies indicating the role of APOE in several diverse diseases of known pathogen cause.
A second putative risk factor is the bacterium, Chlamydia pneumoniae. This pathogen has been identified and localized in AD brain.
Current studies aimed at “proof of principle” address the entry of the organism into the CNS, the neuroinflammatory response to the
organism, and the role that the organism plays in triggering AD pathology. An infection-based animal model demonstrates that following
intranasal inoculation of BALB/c mice with C. pneumoniae, amyloid plaques/deposits consistent with those observed in the AD brain
develop, thus implicating this infection in the etiology of AD.

aIts funny to see that mainstream medical science can purport two seperate causes for such obvious pathologies and yet continue trying to study them seperately.

LittleFighter wrote:I'm ApoE4 (ApoE4 E4/E3). And have the genes for increased chance of balding before 40.

Still searching for my perfect diet, paleo is close. ApoE4 seem to need much more (Dr. BG) like removing metals, more toxin avoidance, more antixodidants, etc.

Is anyone here ApoE4 (if you know!)?

Host responses to infections
involve changes in lipid levels and lipid metabolism in the
plasma. These plasma lipid changes might be mediated by
three cytokines interleukin (IL)-1, IL-6, and tumor necrosis
factor (TNF)-α, which induce elevated levels of triglycerides
and VLDL [22], decreased levels of cholesterol, HDL and
LDL [23, 24] or increased levels of cholesterol in the
serum [25], depending on the nature of the infectious
agents.
Lipoproteins and lipids present in the serum may contribute
to the host innate immunity against pathogens [26].
Studies using apoE deficient mice confirmed the role of
apoE in host susceptibility to endotoxemia and Klebsiella pneumoniae infection [27], while transgenic (Tg) mice
expressing human APOEε3 and APOEε4 genes revealed
an isoform-specific effect of apoE on the proinflammatory
response to lipopolysaccharide (LPS) [28]. Infection of
apoE knockout (KO) mice with Listeria monocytogenes or
Klebsiella pneumoniae leads to an increased susceptibility
to death as well as increased serum levels of TNF-α as
compared with wild-type (WT) mice [29, 30]. Binding of
bacterial endotoxin to either HDL, LDL, or VLDL results
in a redirection of endotoxin uptake from Kupffer cells to
parenchymal hepatocytes where the endotoxin is deactivated
[30]. ApoE facilitated sepsis-induced mortality in a dosedependentmanner
and increased natural killer T-(NKT)-cell
proliferation in the spleen [31]. ApoE deficient mice were
markedly more susceptible to tuberculosis, evidenced by
100% mortality within 4 weeks of infection with tuberculosis
[32].

The Apolipoprotein E (ApoE) 4 Isoform is Associated with an Increased Inflammatory Response in Humans after in vivo Endotoxin Challenge
Stephen Gale, Susette Coyle, Steven Calvano, Siobhan Corbett, and Stephen F. Lowry. Robert Wood Johnson Medical School/University of Medicine and Dentistry of New Jersey

Background: After injury or infection, most patients experience self-limited inflammation; yet others develop hyperinflammation (SIRS/sepsis), worsening morbidity and mortality. Efforts increasingly focus on identifying genetic polymorphisms that may help predict these discrepant outcomes. ApoE, a multifunctional protein with metabolic and immunomodulatory activity, exists as 3 isoforms (ApoE2, E3, or E4) in humans based on allelic inheritance. ApoE3 is most common and has anti-inflammatory properties. The less common ApoE4 is associated with certain inflammatory conditions including Alzheimer disease and cardiovascular disease. Also, animal and human observational studies suggest that ApoE4 is associated with hyperinflammation.

Hypothesis: Healthy human volunteers possessing the ApoE4 allele will demonstrate a greater inflammatory response after in vivo endotoxin challenge than subjects with other isoforms.

Methods: Thirty-six otherwise healthy volunteers were given intravenous endotoxin (2ng/kg) to induce moderate systemic inflammation. Vital signs and blood samples were obtained at various times post-challenge. Plasma TNFα concentrations were assessed by sandwich ELISA. DNA was extracted from the leukocytes at baseline and ApoE isoforms were determined by direct sequencing. Results were analyzed using unpaired t-test.

Results: Of 36 volunteer samples examined, 8 expressed the ApoE4 allele (ApoE4+). Compared to ApoE4- subjects, those ApoE4+ experienced a greater rise in TNFα (p<0.01) and in body temperature (p<0.02) after endotoxin challenge. From the same cohort, 19 subjects were homozygous for the ApoE3 allele (ApoE3/ApoE3); 17 had other allele combinations. The ApoE3 homozygotes had lower TNFα levels (p<0.02) and a lower temperature curve (p<0.02) after endotoxin challenge than all other (AO) subjects either homozygous or heterozygous for ApoE2 or ApoE4.

Conclusions: The ApoE4 allele is associated with a greater inflammatory response after in vivo endotoxin challenge. Subjects homozygous for ApoE3 experienced a less robust inflammatory response after endotoxin challenge when compared to those who are homozygous or heterozygous for ApoE2 or ApoE4. ApoE polymorphism may contribute to differing responses to injury or infection. Genetic testing for ApoE isoforms may help predict which patients will develop hyperinflammation and progress to SIRS or sepsis after injury or infection.

Abstract

Apolipoprotein-E protein is an endogenous immunomodulatory agent that affects both the innate and the adaptive immune responses. Since individuals with the APOE4 gene demonstrate worsened pathology and poorer outcomes in many neurological disorders, we examined isoform-specific differences in the response of microglia, the primary cellular component of the brain's innate immune response, in detail. Our data demonstrate that microglia derived from APOE4/4 targeted replacement mice demonstrate a pro-inflammatory phenotype that includes altered cell morphology, increased NO production associated with increased NOS2 mRNA levels, and higher pro-inflammatory cytokine production (TNFα, IL-6, IL12p40) compared to microglia derived from APOE3/3 targeted replacement mice. The effect is gene dose-dependent and increases with the number of APOE4 gene alleles. The APOE genotype-specific immune profile observed in the microglial immune response is also observed in the cortex of aged APOE3/3 and APOE4/4 mice treated with lipopolysacchride (LPS) and in peripheral (peritoneal) macrophages. To determine if APOE4's action resulted from an isoform-specific difference in effective levels of the apolipoproteins, we generated mice expressing only a single allele of APOE3. Immune-stimulated macrophages from APOE3/0 mice demonstrated an increased inflammatory response compared to APOE3/3 mice, but less than in APOE4/4 mice. These data suggest that inhibition of inflammation depends upon the dose of apoE3 protein available and that apoE4 protein may alter inflammation partly by dose effects and partly by being qualitatively different than apoE3. Overall, these data emphasize the important role of apolipoprotein E and of the APOE genotype on the immune responses that are evident in most, if not all, neurological disease.