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Apolipoprotein E: Essential Catalyst
Serenoa
Posted: Monday, September 8, 2014 5:31 AM
Joined: 4/24/2012
Posts: 484


International Journal of Alzheimer’s Disease, 2012

 

 Abstract

The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

 

http://www.hindawi.com/journals/ijad/2012/489428/

 

 

Dr. Huntington Potter has put forth some very interesting concepts in this article. One concept that I found fascinating is LIPIDATION STATE of the ApoE molecule. This is because of CHOLESTEROL which is something we can all understand and possibly change. Much to digest here and I hope you all might have some feedback. Thanks.

 


Lane Simonian
Posted: Monday, September 8, 2014 9:54 AM
Joined: 12/12/2011
Posts: 4855


There is a more simple and perhaps better explanation for this.  Low density lipid receptors are g-protein coupled receptors.  When slightly stimulated by Apoe2 for instance, amyloid is cleared via the phosphatidylinositol 3-kinase/Akt.  When overstimulated by Apoe4, it leads to the formation of peroxynitrites and the aggregation of amyloid.



Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease


Conclusion: These results imply a functional interaction between ApoE and LDL receptor proteins that determines risk for Alzheimer's disease.


 


Serenoa
Posted: Tuesday, September 9, 2014 5:57 PM
Joined: 4/24/2012
Posts: 484


LDL receptors are key players. What about the lack of b-amyloid toxicity when ApoE4 is not present? I find that very interesting. I want to know how cholesterol or lipidation affects ApoE. I think conformational changes in ApoE4 brought about by lipids/cholesterol may be affecting how it interacts with b-amyloid or LDL receptors. I cannot find much research on this. You got anything? Thanks.
Lane Simonian
Posted: Tuesday, September 9, 2014 7:34 PM
Joined: 12/12/2011
Posts: 4855


Part of the key is oxidative stress.  For those with the Apoe4 gene it is critical to avoid other factors that can increase oxidative stress (salt, sugar, carbohydrates, high fructose corn syrup, smoking, excessive alcohol consumption, sedentary lifestyle, etc.).


 2008 Jan;52(1):131-45. doi: 10.1002/mnfr.200700322.

Impact of apoE genotype on oxidative stress, inflammation and disease risk.

Abstract

Although in developing countries an apolipoprotein E4 (apoE4) genotype may offer an evolutionary advantage, as it has been shown to offer protection against certain infectious disease, in Westernised societies it is associated with increased morbidity and mortality, and represents a significant risk factor for cardiovascular disease, late-onset Alzheimer's disease and other chronic disorders. ApoE is an important modulator of many stages of lipoprotein metabolism and traditionally the increased risk was attributed to higher lipid levels in E4 carriers. However, more recent evidence demonstrates the multifunctional nature of the apoE protein and the fact that the impact of genotype on disease risk may be in large part due to an impact on oxidative status or the immunomodulatory/anti-inflammatory properties of apoE. An increasing number of studies in cell lines, targeted replacement rodents and human volunteers indicate higher oxidative stress and a more pro-inflammatory state associated with the epsilon4 allele. The impact of genotype on the antioxidant and immunomodulatory/anti-inflammatory properties of apoE is the focus of the current review. Furthermore, current information on the impact of environment (diet, exercise, smoking status, alcohol) on apoE genotype-phenotype associations are discussed with a view to identifying particular lifestyle strategies that could be adapted to counteract the 'at-risk' E4 genotype.

 

Interesting, Apoe deficiency also increases oxidative stress without apparently producing amyloid.


 2002 Oct 15;33(:1115-20.

Apolipoprotein E deficiency promotes increased oxidative stress and compensatory increases in antioxidants in brain tissue.

Abstract

The epsilon 4 allele of the apolipoprotein E gene (ApoE) is associated with Alzheimer's disease (AD). The extent of oxidative damage in AD brains correlates with the presence of the E4 allele of ApoE, suggesting an association between the ApoE4 genotype and oxygen-mediated damage in AD. We tested this hypothesis by subjecting normal and transgenic mice lacking ApoE to oxidative stress by folate deprivation and/or excess dietary iron. Brain tissue of ApoE-deficient mice displayed increased glutathione and antioxidant levels, consistent with attempts to compensate for the lack of ApoE. Folate deprivation and iron challenge individually increased glutathione and antioxidant levels in both normal and ApoE-deficient brain tissue. However, combined treatment with folate deprivation and dietary iron depleted antioxidant capacity and induced oxidative damage in ApoE-deficient brains despite increased glutathione, indicating an inability to compensate for the lack of ApoE under these conditions. These data support the hypothesis that ApoE deficiency is associated with oxidative damage, and demonstrate a combinatorial influence of genetic predisposition, dietary deficiency, and oxidative stress on oxidative damage relevant to AD.


Lane Simonian
Posted: Tuesday, September 9, 2014 10:16 PM
Joined: 12/12/2011
Posts: 4855


I am still sorting through this article, but there may be some important clues here:


Transgenic mice expressing apoE4 in astrocytes have impairment of working memory, despite the absence of significant neuropathological changes in the brain [81]. Furthermore, human apoE4 knock-in mice, in which the mouse apoE gene is replaced with the human apoE gene, develop spatial learning and memory deficits not seen in human apoE3 knock-in mice [78,79,81,82]. Since Aβ does not accumulate in any of these apoE isoform transgenic mouse models, these data strongly suggest Aβ-independent roles of apoE4 in causing neuronal and behavioral deficits in vivo.


So maybe the fact that Apoe4 knockout mice don't develop amyloid is irrelevant.  Apoe deficiency is very rare in human beings, and unfortunately few if any of the people with this deficiency live very long lives.


Interestingly, exercise, which stimulates hippocampal neurogenesis, improves cognition and hippocampal plasticity in apoE4 transgenic mice [99].


ApoE4 and its fragments impair mitochondrial function. Mitochondrial dysfunction has been reported in AD, which is modulated by apoE genotype, with a greater effect in apoE4 than in apoE3 carriers [121-124,125]. In both AD patients and age-matched nondemented subjects, apoE4 is associated with decreased cerebral glucose metabolism [126-135], an effect that occurs decades before cognitive impairment become apparent [126,127,136] and, probably, also before significant Aβ deposition. Thus, apoE4 may cause mitochondrial dysfunction at very early stages in life. Mitochondrial dysfunction is clearly coupled with production of reactive oxygen species and increased oxidative damage, which in turn further impair mitochondrial activity. Temporary or sustained loss of mitochondrial function impairs cellular defenses and repair mechanisms, decreasing the ability of neurons to mount an appropriate stress response and causing cellular injury.


Concluding remarks and potential therapeutic strategies
In addition to its well-documented Aβ-dependent roles [157], apoE4 has Aβ-independent roles in the pathogenesis of AD [43,47,48,158]. Independently of Aβ, apoE4 has detrimental effects on neuronal plasticity, undergoes aberrant proteolysis that generates neurotoxic fragments, stimulates tau phosphorylation and disrupts the cytoskeleton, and impairs mitochondrial function (Figure 3). In humans, the Aβ-dependent and Aβ-independent effects of apoE4 can act in concert to exacerbate the pathological and clinical phenotypes of AD.


http://labs.gladstone.ucsf.edu/huang/pages/apoe-research


Here is a link between Apoe4 and p38 Mapk and from there it is just one more step to peroxynitrites.


Inheritance of the three different alleles of the human apolipoprotein (apo) E gene (APOE) are associated with varying risk or clinical outcome from a variety of neurologic diseases. ApoE isoform-specific modulation of several pathogenic processes, in addition to amyloid β metabolism in Alzheimer's disease, have been proposed: one of these is innate immune response by glia. Previously we have shown that primary microglia cultures from targeted replacement (TR) APOE mice have apoE isoform-dependent innate immune activation and paracrine damage to neurons that is greatest with TR by the ε4 allele (TR APOE4) and that derives from p38 mitogen-activated protein kinase (p38MAPK) activity.



http://www.jneuroinflammation.com/content/3/1/10


 2008 May;52(6):1188-97. doi: 10.1016/j.neuint.2007.12.009. Epub 2007 Dec 27.

Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-gamma-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase.

So even without amyloid, Apoe4 produces neurotoxic effects in the absence of exercise or dietary changes.



Serenoa
Posted: Wednesday, September 10, 2014 8:22 PM
Joined: 4/24/2012
Posts: 484


Excellent. That's what I was hoping for. Good clues in those last posts Lane. I've got to digest this new info. Thanks!
Serenoa
Posted: Thursday, September 11, 2014 5:15 AM
Joined: 4/24/2012
Posts: 484


The Absence of ABCA1 Decreases Soluble ApoE Levels but Does Not Diminish Amyloid Deposition in Two Murine Models of Alzheimer Disease

 

Abstract

ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate β-amyloid (Aβ) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable Aβ levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.

 

http://www.jbc.org/content/280/52/43243.short

 

 

Role of LXR and ABCA1 in the Pathogenesis of Alzheimer's Disease -Implications for a New Therapeutic Approach

 

Abstract:

Studies, ranging from epidemiological to in vitro and in vivo experimental settings have provided convincing evidence that different aspects of brain lipid metabolism may influence Alzheimer disease pathogenesis through effects on β-amyloid deposition and clearance. It has been demonstrated that transcription factors called nuclear liver X receptors (LXR) and their responsive genes provide natural regulatory mechanisms and influence AD pathogenesis through their modulatory effects on intracellular cholesterol content, cholesterol efflux and possibly via anti-inflammatory mechanisms. Here, we provide a brief summary of the approaches undertaken by different groups that lead to the nowadays working model of LXR and ABCA1 regulatory role in brain amyloidogenesis and amyloid clearance and we highlight the therapeutic potential of LXR agonists.
 

http://www.ingentaconnect.com/content/ben/car/2007/00000004/00000002/art00015

 

 

Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer's Disease (AD): Relevance to AD Prevention

Abstract

Environmental and genetic factors, notably ApoE4, contribute to the etiology of late-onset Alzheimer's disease (LOAD). Reduced mRNA and protein for an apolipoprotein E (ApoE) receptor family member, SorLA (LR11) has been found in LOAD but not early-onset AD, suggesting that LR11 loss is not secondary to pathology. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate β-amyloid (Aβ). Genetic polymorphisms that reduce LR11 expression are associated with increased AD risk. However these polymorphisms account for only a fraction of cases with LR11 deficits, suggesting involvement of environmental factors. Because lipoprotein receptors are typically lipid-regulated, we postulated that LR11 is regulated by docosahexaenoic acid (DHA), an essential ω-3 fatty acid related to reduced AD risk and reduced Aβ accumulation. In this study, we report that DHA significantly increases LR11 in multiple systems, including primary rat neurons, aged non-Tg mice and an aged DHA-depleted APPsw AD mouse model. DHA also increased LR11 in a human neuronal line. In vivo elevation of LR11 was also observed with dietary fish oil in young rats with insulin resistance, a model for type II diabetes, another AD risk factor. These data argue that DHA induction of LR11 does not require DHA-depleting diets and is not age dependent. Because reduced LR11 is known to increase Aβ production and may be a significant genetic cause of LOAD, our results indicate that DHA increases in SorLA/LR11 levels may play an important role in preventing LOAD.

 


Lane Simonian
Posted: Thursday, September 11, 2014 11:06 AM
Joined: 12/12/2011
Posts: 4855


Now it is my turn to sort through things.  In the meantime, here is a possible route that explains the benefit of DHA: the activation of Akt (perhaps in part through SorLA) and the induction of the brain's master antioxidant: glutathione.


Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival

  1. Mohammed Akbar
  2. Frances Calderon
  3. Zhiming Wen, and 
  4. Hee-Yong Kim *
  1. Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX (received for review April 7, 2005.

Abstract

Phosphatidylinositol 3-kinase [PI (3)K]/Akt signaling is a critical pathway in cell survival. Here, we demonstrate a mechanism where membrane alteration by the n-3 fatty acid status affects Akt signaling, impacting neuronal survival. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid highly enriched in neuronal membranes, promotes neuronal survival by facilitating membrane translocation/activation of Akt through its capacity to increase phosphatidylserine (PS), the major acidic phospholipid in cell membranes. The activation of PI (3)K and phosphatidylsinositol triphosphate formation were not affected by DHA, indicating that membrane interaction of Akt is the event responsible for the DHA effect.

Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells.

(cannot find a direct DHA/Akt/glutathione reference).





Lane Simonian
Posted: Thursday, September 11, 2014 11:48 AM
Joined: 12/12/2011
Posts: 4855


ApoE can activate the phosphatidylinositol 3/Akt kinase through low density lipid receptors, but the increased binding of very low density lipids to these receptors by ApoE4 results in the production of peroxynitrites and Alzheimer's disease.


These results suggest that inheritance of apoE4 is associated with an increased affinity of VLDL particles for LDL receptors on hepatocytes and may partly explain the influence of the E4 isoform on lipid metabolism.


http://www.ncbi.nlm.nih.gov/pubmed/10070023


 2002 Mar 22;292(1):83-7.

Apolipoprotein E activates Akt pathway in neuro-2a in an isoform-specific manner.

Abstract

Apolipoprotein E (apoE) is a ligand for members of the low density lipoprotein (LDL) receptor family, receptors highly expressed in neurons. A study of one of the mechanisms by which apoE might affect neuronal cell metabolism is reported herein. ApoE can induce Akt/protein kinase B phosphorylation in Neuro-2a via two different pathways. Both pathways are mediated by phosphatidylinositol 3-kinase and cAMP-dependent protein kinase. The first pathway is stimulated by apoE3 and E4, but not by E2, after a 1-h incubation. The process requires the binding of apoE to the heparan sulfate proteoglycan/LDL receptor-related protein complex. The second pathway is activated after a 2-h incubation of the cells, in another isoform-dependent manner (E2 = E3 dbl greater-than sign E4) and is mediated by calcium. Our results suggest that apoE might affect cell metabolism and survival in neurons in an isoform-specific manner by inducing novel signaling pathways.


Serenoa
Posted: Friday, September 12, 2014 5:40 AM
Joined: 4/24/2012
Posts: 484


This is good stuff. Could this be evidence for a low-fat diet increasing the risk for AD? What if:

 

ApoE4 + healthy fat in the diet (DHA) = lower risk for AD

and

ApoE2(3) + low-fat diet = higher risk for AD

 

Because we have to address why all with the E4 gene don't get AD, and many with the beneficial E2 gene do get AD

  

Also, the young blood mouse study and anecdotal blood transfusion evidence sticks in my mind as being important. The link to lipids might explain that.

 


Lane Simonian
Posted: Friday, September 12, 2014 9:55 AM
Joined: 12/12/2011
Posts: 4855


This may very well be right.  DHA is likely protective regardless of the Apoe4 status, but saturated fats effects may vary depending on Apoe status.  In regards to the new blood study, I have a feeling something significant is there as well, but would like to know precisely what the new blood contains that the old blood does not that may make it an effective treatment. 


 

The question of fats gets further complicated by polyphenols and carbohydrates.  Many saturated fats coming from plants and dairy products contain polyphenols which help protect the brain against Alzheimer's disease. On the other hand, when people go on a low fat diet they often replace the calories with sugar and carbohydrates which increases the risk for Alzheimer's disease. 


 

I think that changes in the way we consume and process food has significantly increased the incidence of Alzheimer's disease.  Before fructose or sugar may have come in the form of fruits or cocoa rich in polyphenols. Breads and pastas used to contain higher levels of polyphenols and lower levels of gluten.  And then we started consuming products that combined the worse of both such as high fructose corn syrup.  And finally there are environmental contaminants (pesticides, for instance) added to our food.