RSS Feed Print
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Serenoa
Posted: Tuesday, November 27, 2012 5:53 AM
Joined: 4/24/2012
Posts: 484


This research has discovered a second gene, besides ApoE4, that significantly increases the odds of getting AD. What is exciting about this discovery is what is tells us about the causes of AD, and thus how to attack the disease. The main finding of the research is that defects in the TREM2 gene cripple the immune system's ability to remove placks, but also points to the importance of inflammation as a causal factor in AD. TREM2 is apparently like a safety net, a back up mechanism to correct the insults of oxidative damage and inflammation that we know (from Lane's many posts) are probably the ultimate cause of the plack formation in the first place.

 

From the article in the New England Journal of Medicine:

 

Disscussion

Inflammation is a well-established histologic feature in the brains of patients with Alzheimer's disease. Complement factors were identified in amyloid plaques in the 1980s,21,22 followed by reports of clusters of activated microglia, complement-activation products, and cytokines in and near amyloid plaques.23-26 There is evidence that inflammation is an early event in the brains of patients with Alzheimer's disease.27 It has also been noted that the expression of genes associated with inflammation in the brain is increased in aging and that this effect is accentuated in patients with Alzheimer's disease.

 

In brain cells, TREM2 is primarily expressed on microglia, the resident histiocytes of the central nervous system.37 Activation of microglia may lead to phagocytosis of cell debris and amyloid, but microglia can also be activated to promote the production of proinflammatory cytokines, or they may differentiate into antigen-presenting cells.38 A recent study showed that TREM2 expression is induced concomitantly with the formation of amyloid plaques in APP transgenic mice expressing the Swedish mutation (K670N/M671L) in APP,39 and this expression was found to correlate positively with amyloid phagocytosis by unactivated microglia.

 

The expression of TREM2 also correlated positively with the ability of microglia to stimulate the proliferation of CD4+ T cells, as well as the secretion of tumor necrosis factor and CCL2, but not interferon-γ, into the extracellular milieu. This led the authors to speculate that TREM2-positive microglia on plaques capture and present self-antigens to lymphocytes infiltrating the central nervous system without promoting proinflammatory responses.39 Furthermore, knockdown of TREM2 or DAP12 in microglia resulted in reduced phagocytosis of apoptotic neurons, whereas the overexpression of TREM2 increased such phagocytosis,40 suggesting that microglia recognize and phagocytose apoptotic neurons through TREM2 ligation. TREM2 has an antiinflammatory function; it inhibits macrophage response to ligation of toll-like receptor (TLR),41 and it negatively regulates TLR-mediated maturation of dendritic cells, type I interferon responses, and the induction of antigen-specific T-cell proliferation.36

Furthermore, TREM2 stimulation of dendritic cells induces partial activation without any production of proinflammatory cytokines.

 

http://www.nejm.org/doi/full/10.1056/NEJMoa1211103#t=articleDiscussion

 

 

 


Lane Simonian
Posted: Tuesday, November 27, 2012 10:10 AM
Joined: 12/12/2011
Posts: 4854


Thank you for posting about this important discovery, Serenoa.  Three of the major genetic risk factors for Alzheimer's disease: presenilin gene mutations, the APOE4 gene, and TREM2 genetic defects all inhibit the same pathway: the phosphatidylinositol-3 kinase/Akt pathway.  This is a cell survival pathway and can lead to inflammation and immune responses.  Cutting off of this pathway leads to the formation of peroxynitrites which nitrate amyloid plaques and increase their aggregation.  This impedes the breakdown and removal of amyloid plaques.  Peroxynitrites also nitrate tau proteins impeding  their breakdown following hyperphosphorylation.  Peroxynitrites also cause inflammatory responses. 

 

http://www.ncbi.nlm.nih.gov/pubmed/8856840 

 

One inflammatory pathway is knocked down in Alzheimer's disease; another is ramped up.  And oxidative damage is widespread.  Neutralize the oxidant (peroxynitrite) and repair part of its damage and you can partially treat Alzheimer's disease.   


Serenoa
Posted: Tuesday, November 27, 2012 10:04 PM
Joined: 4/24/2012
Posts: 484


Are you sure that TREM2 is involved in the phosphatidylinositol-3 kinase/Akt pathway? Did the article point to that? I couldn't find a reference to it. Does one of the following excerpts point to it?

  

 TREM2 is a transmembrane glycoprotein, consisting of an extracellular immunoglobulin-like domain, a transmembrane domain, and a cytoplasmic tail, which associates with DAP12 for its signaling function.32,34 TREM2 has both exogenous ligands on pathogens and endogenous ligands that remain largely unknown, although a recent study has shown that Hsp60 is an agonist of TREM2 in neuroblastoma cells and astrocytes.35 In addition, an endogenous ligand on dendritic cells has been found.

 

In brain cells, TREM2 is primarily expressed on microglia, the resident histiocytes of the central nervous system.37 Activation of microglia may lead to phagocytosis of cell debris and amyloid

 

The expression of TREM2 also correlated positively with the ability of microglia to stimulate the proliferation of CD4+ T cells, as well as the secretion of tumor necrosis factor and CCL2, but not interferon-γ, into the extracellular milieu.

 

Thanks Lane, I really appreciate your feedback.


Lane Simonian
Posted: Tuesday, November 27, 2012 10:49 PM
Joined: 12/12/2011
Posts: 4854


My fault, Serenoa.  Sometimes, I worry about posting too many studies but I should not worry about that--since it is better to over-inform than to under-inform. 

 

Furthermore, TREM-2-mediated Akt activation and proliferation of osteoclast precursor cells were also enhanced in TLT-1s silenced cells.

 

http://www.jbc.org/content/early/2012/07/03/jbc.M112.351239 

 

TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.

 

http://www.ncbi.nlm.nih.gov/pubmed/20484116 

 

The osteoporosis drug Fosamax (an alendronate) inhibits the same pathway (as with TREM defects) and likely also increases the risk for Alzheimer's disease. 

 

The present findings demonstrate that alendronate inhibited the PI3K-Akt-NFkappaB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.

 

http://www.ncbi.nlm.nih.gov/pubmed/16100524 

 

Presenilin gene mutations basically cut off this pathway and leads to early onset Alzheimer's disease (Familial Alzheimer's Disease). 

 

Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.

 

http://www.nature.com/emboj/journal/v23/n13/abs/7600251a.html 

 

Lastly to a lesser effect that presenilin gene mutations, the APOE4 gene also inhibits this pathway (thus having the APOE gene does not guarantee that one will get Alzheimer's disease). 

 

APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2.

 

http://www.ncbi.nlm.nih.gov/pubmed/16973905 

 

The inhibition of the phosphatidylinositol-3 kinase/Akt pathway most probably increases the risk for Alzheimer's disease. 

 

 

 

 


Serenoa
Posted: Tuesday, November 27, 2012 11:34 PM
Joined: 4/24/2012
Posts: 484


Excellent! More evidence. Thank you Lane.

 

Now check out this new research I just heard on NPR about another potential treatment. I'd like to know if it fits with what we know about Phosphoplipase C/Protien Kinase C pathway (bad) and the phosphatidylinositol-3 kinase/Akt pathway (good). I reviewed your previously posted pathway diagrams (which are great) but didn't see the connection. They are claiming that blocking the P40 molecule, which is a component of cytokines interleukin (IL)-12 and -23,reduces amyloid deposits. Ustekinumab, which blocks P40, is approved by the United States Food and Drug Administration to treat psoriasis. My question is this, does interleukin 12 or 23 play a part in either of these pathways.

 

Here is the article (sorry I haven't figure out how the do the hyperlink):

 

http://www.mediadesk.uzh.ch/articles/2012/alzheimer-erkrankung-bei-maeusen-gemildert--aussichtsreicher-therapieansatz-fuer-menschen_en.html

 

They "were able to show that turning off particular cytokines (immune system signal transmitters) reduced the Alzheimer’s typical amyloid-ß deposits in mice with the disease. As a result, the strongest effects were demonstrated after reducing amyloid-ß by approximately 65 percent, when the immune molecule p40 was affected, which is a component of the cytokines interleukin (IL)-12 and -23."

 

"the level of p40 molecules is higher in Alzheimer’s patients’ brain fluid, which is in agreement with a recently published study by American colleagues demonstrating increased p40 levels in blood plasma of subjects with Alzheimer’s disease"

 

"The significance of the immune system in Alzheimer’s research is the focus of current efforts. Prof. Heppner and Prof. Becher suspect that cytokines IL-12 and IL-23 themselves are not causative in the pathology, and that the mechanism of the immune molecule p40 in Alzheimer’s requires additional clarification"

 

Also, here's the psoriasis drug:

 

http://www.ncbi.nlm.nih.gov/pubmed/20430307

 

 


Lane Simonian
Posted: Wednesday, November 28, 2012 12:26 AM
Joined: 12/12/2011
Posts: 4854


NADPH oxidase increases interleukin-12 levels and more importantly it increases levels of superoxide anions that combine with inducible nitric oxide to produce peroxynitrites. 

 

http://www.ncbi.nlm.nih.gov/pubmed/11913532 

 

The pathway that leads to the production of superoxide anions and inducible nitric oxide is via Protein kinase C (Protein kinase C--MAPK--tumor necrosis factor alpha).   

 

http://www.ncbi.nlm.nih.gov/pubmed/10728373 

 

Initially interleukin-12 increases phospholipase C beta activation which further increases Protein kinase C activation and the formation of peroxynitirtes.  It is just one negative feedback system after another. 

 

http://www.ncbi.nlm.nih.gov/pubmed/11743656 

 

A P40 inhibitor might initially reduce the interleukin-12 activation of phospholipase C beta which would in turn inhibit the release of intracellular calcium and lessen the activity of the calcium-dependent enzyme which cleaves amyloid plaques.  It would also inhibit the formation of peroxynitrites lessening the nitration of amyloid plaques, allowing for their increased clearance. 


Serenoa
Posted: Friday, December 14, 2012 8:46 AM
Joined: 4/24/2012
Posts: 484



I must admit that my understanding of all this terminology and biological functioning is very limited. Even though I have a degree in Biology, it all seems overwhelmingly complex, which is why it is so great to have this forum with knowledgeable folks to share research with and help sort it all out.

 

Through the fog that clouds my understanding of these complex mechanisms, I try to focus on more generalized concepts that I can wrap my brain around.

As I have searched for clues to the cause of this disease, one of the questions that pops up is: why does both stimulating as well as suppressing the immune system seem to provide benefits to AD (Alzheimer’s Disease)? It seems counter intuitive.

 

My interest in this line of thinking originates from my mother's involvement with the IgIV clinical trial and, in particular, the improvements she experienced with off label use of the GM-CSF (granulosite macrophage – colony stimulating factor) Leukine. Both are used to boost a weakened or deficient immune system, but one would think they would also increase inflammation as part of the immune response. Inflammation is a major cause of damage in AD pathology, and thus anti-inflammatory and immune suppressants have also been shown to benefit AD. We see this in other autoimmune type diseases like Rheumatoid Arthritis.

 

I just found a fascinating article that shows G-CSF (similar to GM-CSF, an immune system booster) actually helped patients with an inflammation driven disease! And, it proposes an answer to my dilemma saying, "inflammation represents a secondary response to a primary deficiency of innate immunity."

An open-labelled study of granulocyte colony-stimulating factor in the treatment of active Crohn's disease (2005)

 http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2005.02287.x/full

  

 Results

“This pilot study offers preliminary evidence that rhuG-CSF is a safe and potentially effective therapy for the treatment of active CD. About 25% (five of 20) of patients achieved remission during the study and additional patients demonstrated a significant improvement for an overall improvement observed in 55% (11 of 20). We observed a beneficial response in patients with fistulizing disease as well.”

  

 Introduction

 “While the fundamental aetiology of Crohn's disease (CD) remains unknown, the prevailing hypothesis contends that CD results from an aberrant, T cell-driven process activated by unknown stimuli. Most current and investigational therapies for CD aim to suppress the immune system to restore health. Established medical strategies for treatment of the intestinal inflammation of CD include broadly acting immunosuppressive agents such as corticosteroids, methotrexate, azathioprine or mercaptopurine (6-mercaptopurine). Recent therapeutic innovations, such as infliximab, have been designed to be more selective, interfering with specific elements of the inflammatory cascade.

“An alternate understanding is that the characteristic intestinal inflammation represents a secondary response to a primary deficiency of innate immunity. This concept is suggested by the association of CD with genetic diseases, such as chronic granulomatous disease (CGD), glycogen storage disease Ib (GSDIb), and cyclic neutropenia, among others, in which a variety of qualitative or quantitative neutrophil deficiencies or other defects in innate immunity have been well characterized.1–18 These associations infer that a Crohn's phenotype may be initiated by a deficiency in neutrophil or monocyte function which, in turn, leads to chronic inflammation in which macrophage and eventually T-cell activation may occur as a sequential mucosal immune response to compensate for the deficiency in innate immunity.19”

 

 


Lane Simonian
Posted: Friday, December 14, 2012 12:38 PM
Joined: 12/12/2011
Posts: 4854


I do not have a good answer for the role of inflammation in Alzheimer's disease.  The disease stimulates a pathway that increase immune responses/inflammation (protein kinase C--MAPK--NFkB--peroxynitrites); and it decreases a pathway that increases immune responses/inflammation (phosphatidylinositol 3 kinase/Akt--MAPK--NFkB).  Perhaps it does not matter, if you scavenge peroxynitrites, the immune system returns closer to normal.   
Lane Simonian
Posted: Friday, December 14, 2012 2:28 PM
Joined: 12/12/2011
Posts: 4854


I have to repivot again.  In some case, Akt can suppress MAP-kinases so in Alzheimer's disease with the cutting off the Akt pathway and stimulating the protein kinase C pathway, a person may get a double dose of inflammation. 

 

http://www.jbc.org/content/277/35/32124.full 

 

The protein kinase C activation of the MAP-kinase p38 is a critical step in Alzheimer's disease because it leads not only to inflammation but to the chief oxidant in Alzheimer's disease: peroxynitrites. 

 

2010 Mar;58(3):561-8. doi: 10.1016/j.neuropharm.2009.11.010. Epub 2009 Dec 4.

Targeting p38 MAPK pathway for the treatment of Alzheimer's disease.

Source

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. lmunoz@pharm.usyd.edu.au

Abstract

Accumulating evidence indicates that p38 mitogen-activated protein kinase (MAPK) could play more than one role in Alzheimer's disease (AD) pathophysiology and that patients suffering from AD dementia could benefit from p38 MAPK inhibitors. The p38 MAPK signalling has been widely accepted as a cascade contributing to neuroinflammation. However, deepening insight into the underlying biology of Alzheimer's disease reveals that p38 MAPK operates in other events related to AD, such as excitotoxicity, synaptic plasticity and tau phosphorylation. Although quantification of behavioural improvements upon p38 MAPK inhibition and in vivo evaluation of p38 MAPK significance to various aspects of AD pathology is still missing, the p38 MAPK is emerging as a new Alzheimer's disease treatment strategy. Thus, we present here an update on the role of p38 MAPK in neurodegeneration, with a focus on Alzheimer's disease, by summarizing recent literature and several key papers from earlier years.

 

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.

Source

Department of Pharmacology, College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea

 

Our results suggest that activated p38 MAPK may serve as a potential signaling molecule in ONOO(-) generation through dual regulatory mechanisms, involving iNOS induction and NADPH oxidase activation.

 

I am almost certain of the pathway that leads to Alzheimer's disease now.


Lane Simonian
Posted: Saturday, December 15, 2012 11:36 AM
Joined: 12/12/2011
Posts: 4854


Ah, yes, this is the research that I have been looking for. 

 

2005 Jan;20(1):299-315.

Activating Akt and the brain's resources to drive cellular survival and prevent inflammatory injury.

Source

Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. [My mother graduated from Wayne State University.  How appropriate!]. 

 

 

http://www.ncbi.nlm.nih.gov/pubmed/15578447 

 

Most of the genetic factors in Alzheimer's disease: TREM2 deficiencies, the APOE4 gene, and presenilin gene mutations inhibit or cut off the Phophatidylinositol-3 kinase/Akt as does the bisphosphonate alendronate drug Fosamax (and other similar osteoporosis drugs).   

 

http://www.ncbi.nlm.nih.gov/pubmed/16100524 

 

And now the critical diagram for Alzheimer's disease. 

 

   

 

       

Skip the MAPK pathway from Akt, as it apparently does not apply to the brain.  Inhibit the pathway on the left side of the chart and you prevent or delay the onset of Alzheimer's disease.  Scavenge and repair part of the damage done by peorxynitrites (the endpoint of the pathway) and you effectively treat Alzheimer's disease.  If anyone on these boards or administrators have any contacts within the research staff at the Alzheimer's Association please have them do something about this disease based on this information.  In its current form it is a done disease. 


 

 

 

 

 


Serenoa
Posted: Monday, December 17, 2012 9:49 PM
Joined: 4/24/2012
Posts: 484


OK, lets talk about the phosphatidylinositol 3 kinase/Akt pathway as it may relate to an impaired immune response. If I am right about Crohn’s disease and Alzheimer’s having a similar cause then we must consider that GM-CSF/G-CSF may be beneficial for Alzheimer’s too. So, is there a connection between GM-CSF and the phosphatidylinositol 3 kinase/Akt pathway? 

First let’s look at some relevant excerpts from my previously posted study:  

  

An open-labeled study of granulocyte colony-stimulating factor in the treatment of active Crohn's disease (2005) 

 

 http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2005.02287.x/full 

 

“Inadequate neutrophil function has been previously characterized in CD including a deficiency of chemotaxis, response to complement, and microbicidal and candicidal killing.31, 36–41 These neutrophil abnormalities may represent the primary defect in CD which potentially stems from an immune deficiency rather than an excessively activated response. The 3020insC mutation in the NOD2 gene, recently identified to be linked with CD, is associated a deficient response of NFκ-B when stimulated by lipopolysaccharide.42 This observation suggests a possible defect in the innate immune system may be responsible for at least some cases of CD. This model suggests a shift in the therapeutic paradigm from one of immunosuppression to focused immune stimulation for the treatment of CD directed towards improving innate immunity. Targeted stimulation of specific aspects of innate immune function may be most appropriate for a subgroup of patients having a defect in their innate immunity.

  

Both G-CSF and GM-CSF have been suggested to be beneficial in open-labelled pilot trials. Both rhuGM-CSF and rhuG-CSF were selected for study because of their known direct effects of its broad augmentation of neutrophil function, including chemotaxis, superoxide generation and bactericidal killing.27–29 While the benefit noted in this trial might be due to its influence on neutrophil function, as this therapy runs counter to most other therapies in CD, important questions include possible mechanisms of action. Functional and mechanistic studies were not performed in this trial. Unlike GM-CSF, G-CSF has been suggested to act through a number of other immunomodulatory pathways, possibly functioning not as a stimulant of innate immunity alone but also to suppress certain aspects of immune response.” 

 

Now here is some research I found linking GM-CSF/G-CSF to phosphatidylinositol 3 kinase/Akt: 

Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): evidence for the role of a tyrosine kinase activity distinct from the janus kinases

“Granulocyte colony-stimulating factor (G-CSF) regulates the proliferation, differentiation, and survival of neutrophilic granulocytes. G-CSF exerts its actions by stimulating several signaling cascades after binding its cell surface receptor. Both Jak (Janus) and Src families of tyrosine kinases are stimulated by incubation of cells with G-CSF. In this report, we show that G-CSF stimulation of cells leads to activation of Akt. The membrane-proximal 55 amino acids of the G-CSF receptor cytoplasmic domain are sufficient for mediating Akt activation. However, activation of Akt appears to be downregulated by the receptor's carboxy-terminal region of 98 amino acids” 

 

http://bloodjournal.hematologylibrary.org/content/95/5/1656.short 

G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth

“Granulocyte colony-stimulating factor (G-CSF) drives the production, survival, differentiation, and inflammatory functions of granulocytes. Reactive oxygen species (ROSs) provide a major thrust of the inflammatory response, though excessive ROSs may be deleterious. G-CSF stimulation showed a time- and dose-dependent increase in ROS production, correlating with activation of Lyn and Akt. Inhibition of Lyn, PI3-kinase, and Akt abrogated G-CSF-induced ROS production. This was also blocked by DPI, a specific inhibitor of NADPH oxidase. Following G-CSF stimulation, neutrophils from Lyn-/- mice produced less ROSs than wild-type littermates. G-CSF induced both serine phosphorylation and membrane translocation of p47phox, a subunit of NADPH oxidase… The antioxidant N-acetyl-l-cysteine diminished G-CSF-induced ROS production and cell proliferation by inhibiting Akt activation. These data suggest that the G-CSF-induced Lyn-PI3K-Akt pathway drives ROS production. One beneficial effect of therapeutic targeting of Lyn-PI3K-kinase-Akt cascade is abrogating ROS production.” 

 

http://bloodjournal.hematologylibrary.org/content/107/5/1847.short 

 

I would like to know why GM-CSF seems to work in Alzheimer’s. The last two above studies seem to contradict each other regarding the G-CSF – PI3 kinase/Akt connection from what I can decipher. Can you shed some more light on all this? A deficiency in the innate immune system (like neutrophil dysfunction) is making a lot of sense to me these days. 

  

I am considering doing the GM-CSF treatment again with mom but it’s very expensive and I want to find solid evidence that backs up the relatively dramatic (but anecdotal) improvements mom experienced with it last time. Thanks.

 


Lane Simonian
Posted: Monday, December 17, 2012 10:33 PM
Joined: 12/12/2011
Posts: 4854


For reasons I don't understand, the activation of the phosphatidylinositol-3 kinase/Akt pathway increases the production of oxidants and inflammation in some parts of the body, but does the opposite in the brain.

 

 

The PI3K-Akt pathway has been shown to regulate negatively NF-κB and the expression of inflammatory genes. Wortmannin, a specific inhibitor of PI3K, enhanced LPS-induced nitric-oxide synthase in murine peritoneal macrophages (18), and activation of PI3K-Akt suppressed LPS-induced lipoprotein lipase expression in J774 macrophages (24). Induction of nitric-oxide synthase in C6 glial cells and rat primary astrocytes was also regulated negatively by activation of PI3K (17), and a constitutively active PI3K inhibited induction of nitric-oxide synthase gene expression in human astrocytes (25). Angiopoeitin-1, a potent activator of PI3K, negatively regulated vascular endothelial growth factor- and TNF-α-induced TF expression in endothelial cells (26). Finally, in endothelial cells the PI3K-Akt pathway limited vascular endothelial growth factor activation of the p38 MAPK pathway and TF gene expression (27).

 

In contrast to studies showing that the PI3K-Akt pathway negatively regulates expression of inflammatory genes in macrophages, a recent study demonstrated that the PI3K-Akt pathway positively regulated nuclear factor (NF)-κB-dependent gene expression in HepG2 cells via phosphorylation and increased transactivation activity of p65 (28). Overexpression of a constitutively active form of Akt also increased NF-κB-dependent gene expression in 3T3 fibroblasts via the activation of I-κB kinase and the p38 MAPK (29). Activation of PI3K-Akt has been implicated in playing a pivotal role in cytokine-induced transcriptional activation of NF-κB- and AP-1-dependent gene expression and in inhibiting apoptosis (30-34). Finally, activation of the TLR2 receptor in human monocytic cells by Gram-positive bacteria activated the PI3K-Akt pathway and increased the transactivation activity of p65 (35).

 

http://www.jbc.org/content/277/35/32124.full 

 

So if as it appears GM-CSF stimulates the PI3-Akt pathway in the brain, it would have some benefit in the treatment of Alzheimer's disease. 

 

 


Serenoa
Posted: Tuesday, December 18, 2012 8:41 PM
Joined: 4/24/2012
Posts: 484


This is interesting. Since this LPS molecule seems to keep coming up in association with inflammation.

 

 Lipopolysaccharide in APP Transgenic Mice

Abstract

Inflammation has been argued to play a fundamental role in the pathogenesis of Alzheimer’s disease. Mice transgenic for mutant human amyloid precursor protein (APP) develop progressive amyloid deposition, gliosis, and cognitive impairment. Paradoxically, intracranial administration of lipopolysaccharide (LPS) to promote neuroinflammation results in a reduction in amyloid-β peptide (Aβ) burden concurrent with the inflammatory response. To determine whether microglia mediate Aβ clearance after LPS, we used dexamethasone to inhibit the microglial response. Amyloid precursor protein mice were injected intrahippocampally with either LPS or saline and were allowed to survive for 7 days with or without dexamethasone cotreatment. Brain tissue was then analyzed by immunohistochemistry. Hippocampal Aβ burden was reduced 7 days after LPS injection, and this was prevented by cotreatment with dexamethasone. Markers of microglial activation [CD45, complement receptor 3 (CR3), and macrosialin (CD6] were increased by LPS, and these increases were attenuated by dexamethasone. Dexamethasone failed to block LPS-induced increases in all microglial markers, and Fcγ receptors II/III and scavenger receptor A were increased by LPS but were unaffected by dexamethasone cotreatment. These results indicate a complex response by microglia to acute LPS treatment, with only some responses sensitive to steroidal anti-inflammatory drug treatment. Nonetheless, microglial activation was necessary to remove Aβ in this model of neuroinflammation.


Serenoa
Posted: Tuesday, December 18, 2012 8:52 PM
Joined: 4/24/2012
Posts: 484


OK, it just gets weirder. Here is an explanation of failures of anti-inflammatory therapies.

  

 

 LPS- induced inflammation exacerbates phosphotau
pathology in rTg4510 mice (2010)

Abstract
Inflammation and microglial activation are associated with Alzheimer’s disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein
(APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Ab. These studies examined the role of LPS-induced
inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in
several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to nontransgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received
LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Ab by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients.

 

http://www.biomedcentral.com/content/pdf/1742-2094-7-56.pdf

 


Lane Simonian
Posted: Wednesday, December 19, 2012 12:04 AM
Joined: 12/12/2011
Posts: 4854


The problem here is what type of system you are looking at.  LPS activates phospholipase C which triggers intracellular calcium release and the formation of amyloid plaques.   

 

“We have found that after several injections with LPS toxin, (seven consecutive days of LPS administration) mice showed significant elevation in amyloid beta levels in their brains,” said Chumley. “This elevation corresponds with a decreased ability to learn simple tasks.”

 

http://www.brainphysics.com/news/research/role-of-amyloid-plaque-in-ad 

 

http://www.ncbi.nlm.nih.gov/pubmed/10072552 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC43811/ 

 

More importantly, phospholipase C activates protein kinase C which activates MAPK which leads to the production of peroxynitrites. 

 

http://www.ncbi.nlm.nih.gov/pubmed/18289732 

 

Peroxynitrites contribute to the aggregation of plaques via nitration. 

 

http://www.ncbi.nlm.nih.gov/pubmed/21903077 

 

Peroxynitrites also play a critical role in the hyperphosphorylation and nitration of tau proteins.   

 

http://www.ncbi.nlm.nih.gov/pubmed/16816118 

 

To the extent that anti-inflammatories don't work for Alzheimer's disease it is likely they don't work because either they do not sufficiently inhibit the formation of peroxynitrites or they do not effectively scavenge peroxynitrites 

 

Now these scientists casting doubts on these pathways must be looking at something.  For example, I have seen studies suggesting that protein kinase C activation is helpful in protecting against Alzheimer's disease.  The best I have been able to find so far is this chart and explanation which suggests the activation of phospholipase C (by LPS, for instance) is mainly a problem in regards to the formation of amyloid plaques when there are lipid rafts, otherwise it promotes a type of processing of APP which inhibits the formation of amyloid plaques. 

 

Modulation of proteolytic processing of β-amyloid precursor protein (APP) by lipids  

(a) The β-amyloid precursor protein (APP) undergoes amyloidogenic processing mediated either by β- and γ-secretases to yield amyloid β-peptide (Aβ) (purple rectangles). Amyloidogenic processing of APP largely occurs in lipid rafts. Cholesterol and LRP, an ApoE receptor, promote the localization of BACE1 to lipid rafts. GGPP (a short chain isoprenoid) has been shown to promote the association of the γ-secretase complex with lipid rafts. Several lipids (shown in bold text) and lipid metabolizing proteins (italicized bold text) influence APP processing through a variety of mechanisms. (b) APP is also subjected in neurons to a non-amyloidogenic pathway mediated by α-secretase. Localization of APP to non-lipid raft compartments favors processing by α-secretase. Isoprenoids, diaglycerol and phospholipase C (PLC) have been shown to promote the non-amyloidogenic pathway. (c) The relative abundance or absence of the lipids listed on the figure directly influences the activity of BACE1 or γ-secretase. Increased levels of cholesterol or ceramide enhance the activity of BACE1. Cholesterol and sphingolipids are positive modulators of γ-secretase activity while SMase and PLD1 have been identified as negative modulators of γ-secretase activity. PLC-mediated hydrolysis of PtdIns(4,5)P2 promotes amyloidogenesis by stimulating γ-secretase activity and PtdIns(4,5)P2 has been shown to directly inhibit γ-secretase activity.

 

An external file that holds a picture, illustration, etc.
Object name is nihms-367430-f0003.jpg Object name is nihms-367430-f0003.jpg 


Serenoa
Posted: Wednesday, December 19, 2012 7:20 PM
Joined: 4/24/2012
Posts: 484


 Thanks Lane. Wow, I'm in over my head. It's very hard to digest all this research and make sense of it, but I'm trying. Let me focus on microglia, because I feel like I need to understand what's going on with them better. The following is from the original post TREM2 study:

  

 "In brain cells, TREM2 is primarily expressed on microglia, the resident histiocytes of the central nervous system.  The expression of TREM2 also correlated positively with the ability of microglia to stimulate the proliferation of CD4+ T cells, as well as the secretion of tumor necrosis factor and CCL2, but not interferon-γ, into the extracellular milieu. This led the authors to speculate that TREM2-positive microglia on plaques capture and present self-antigens to lymphocytes infiltrating the central nervous system without promoting proinflammatory responses."

 

I am still digesting all this, but here is an article that may progress our understanding of all things microglia.

Neuroprotective role of the innate immune system by microglia

Abstract

" Innate immunity is a rapid series of reactions to pathogens, cell injuries and toxic proteins. A key component of this natural response is the production of inflammatory mediators by resident microglia and infiltrating macrophages. There is accumulating evidence that inflammation contributes to acute injuries and more chronic CNS diseases, though other studies have shown that inhibition of microglia is, in contrast, associated with more damages or less repair. The controversies regarding the neuroprotective and neurodegenerative properties of microglia may depend on the experimental approaches. Neurotoxic substances are frequently used to produce animal models of acute injuries or diseases and they may activate microglia either directly or indirectly by their ability to cause neuronal death and demyelination. Whether microglia and the immune response play a direct role in such processes still remains an open question. On the other hand, there are data supporting the role of resident microglia and those derived from the bone marrow in the stimulation of myelin repair, removal of toxic proteins from the CNS and the prevention of neurodegeneration in chronic brain diseases. The ability of glucocorticoids to provide a negative feedback on nuclear factor kappa B pathways in microglia may be a determinant mechanism underlying the ultimate fate of the inflammatory response in the CNS. This review presents new concepts regarding the neuroprotective role of the innate immune response in the brain and how microglia can be directed to improve recovery after injuries and prevent/delay neurodegeneration."

 

http://www.sciencedirect.com/science/article/pii/S0306452207002588

 

 

   


Lane Simonian
Posted: Wednesday, December 19, 2012 11:17 PM
Joined: 12/12/2011
Posts: 4854


I have been over my head on this disease for eight years, so don't worry about it Serenoa.  Seemingly contradictory results and inconclusive findings have driven me slightly nuts over the years. And I still don't know exactly what role inflammation plays in Alzheimer's disease.  The role of oxidants in Alzheimer's disease is much clearer to me.   

 

Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration.

Biochemistry Department, University of Cambridge, Cambridge, CB2 1QW, UK.
Journal of Neuroinflammation (impact factor: 3.83). 10/2005; 2:20. DOI:10.1186/1742-2094-2-20
 
These results suggest a dual-key mechanism, whereby glial iNOS or microglial NOX [NADPH oxidase] activation alone is relatively benign, but if activated simultaneously are synergistic in killing neurons, through generating peroxynitrite. This mechanism may mediate inflammatory neurodegeneration in response to cytokines, bacteria, ATP, arachidonate and pathological prions, in which case neurons may be protected by iNOS or NOX inhibitors, or scavengers of NO, superoxide or peroxynitrite.
 

 

 

Whether microglia are up-regulated or down-regulated in Alzheimer's disease; whether there is a big immune response or little immune response; whether microglia are "good" or "bad" may not even be relevant.  If you prevent the formation of peroxynitrites, you prevent Alzheimer's disease.  If you scavenge and repair part of the damage done by peroxynitrites, you can effectively treat Alzheimer's disease. 

 

 

 


Lane Simonian
Posted: Thursday, December 20, 2012 10:21 AM
Joined: 12/12/2011
Posts: 4854


I am going to take another shot at this.  First an extract reinforcing the point that peroxynitrites are the key mediator of Alzheimer's disease. 

 

 
 

 

 
Peroxynitrite Mediates Neurotoxicity of Amyloid β-Peptide1–42- and Lipopolysaccharide-Activated Microglia
  1. Valter D. Longo1, *  

+ Author Affiliations

  1. 1 Division of Biogerontology, Andrus Gerontology Center, and Department of Biological Sciences, and
     
  2. 2 Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90089
     
 

Abstract

The amyloid β-peptide (Aβ) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor α (TNF-α), which can be either neurotoxic or neuroprotective. We show that neuron death in cocultures of rat cortical microglia and neurons activated by lipopolysaccharide (LPS) or Aβ1–42 plus interferon γ (IFNγ) is caused by short-lived diffusible molecules and follows the generation of superoxide and/or peroxynitrite as determined by electron paramagnetic spectroscopy. Neurotoxicity induced by LPS or Aβ1–42 plus IFNγ is blocked by inhibitors of NO synthesis and by the peroxynitrite (ONOO−) decomposition catalysts FeTMPyP [5,10,15,20-tetrakis(n-methyl-4′-pyridyl)porphinato iron (III) chloride] and FeTPPS [5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride] but not by the TNF-α inhibitor pentoxifylline. The specificity of FeTMPyP for ONOO− was confirmed by its ability to block the toxicity of a peroxynitrite donor but not of NO donors or of high levels of superoxide in a yeast mutant lacking superoxide dismutase 1. These results implicate peroxynitrite as a mediator of the toxicity of activated microglia, which may play a major role in Aβ1–42 neurotoxicity and Alzheimer's disease.

 

Peroxynitrites activate microglia via the release of glutamate.  Activated microglia increase production of glutamate, peroxynitrites and the critical antioxidant glutathione.  But peroxynitrites deplete glutathione.  In essence, peroxynitrites short-circuit the body's main defense against it. 

  

http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.2000.0741989.x/abstract 


Lane Simonian
Posted: Thursday, December 20, 2012 10:37 AM
Joined: 12/12/2011
Posts: 4854


Here is another possibility--microglia initially increase glutathione production, which scavenges peroxynitrites, which reduces the nitration and aggregation of amyloid plaques, and initially increases their clearance.  But as the levels of glutathione decrease, the reverse happens and amyloid plaques further aggregate.  This might explain why microglia activation seems in some studies to have a beneficial effect, but in other studies a negative effect in regards to amyloid plaques. 

 

https://docs.google.com/viewer?a=v&q=cache:gMBETyBBrgkJ:www.glutathioneexperts.com/pdfs/glutathione-alzheimers-1.pdf+glutathione+amyloid+plaque+removal&hl=en&gl=us&pid=bl&srcid=ADGEESieOjDkpho8TZXK9DWCHxhKNTLGTHRB2f8VI2mrZUKchCYJi1sV72_jszMoo9OK1_ms2AsTUU36whPHCci277syyWlgE3SaHwrG2yVQwdGFn2VhTHOzPGyMSTGSbJn-_B_Y96mE&sig=AHIEtbSONCIlCZdL8JOdJ08WWGDtEgyuSw