Why is Myo-inositol (or just inositol) levels increased in Alzheimer's disease (indicating a possible link between it and the disease) and yet it is naturally produced by the body and important to healthy functioning. It's in the B vitamin family and is widely used as a supplement. I think I know. If Alz is an inflammatory disease, it makes sense. Astrocytosis (immune system activation in the brain that causes inflamation) makes the astrocytes (brain immune cells) produce myo-inositol. This leads to Amyloid deposition and altered APP processing. So, myo-inositol is not a "bad guy" it is just part of the inflammatory process in the body that is reacting to some other factor (like a virus). Down Syndrome also has excess levels of myo-inositol and develop Alz. That is due to the myo-inositol gene being on the 21 chromosome. How is this tied to inflammation? What is the link between infection, Down's, and other things that cause high myo-inositol levels (like high blood sugar)? Here's a study connecting myo-inositol to astrocytosis:

Background

Conclusions

http://www.alzheimersanddementia.com/article/S1552-5260%2813%2900696-1/fulltext

That the immune response often precedes amyloid deposition is an important finding.  Chronic bacteria and viral infections can both provoke this response.

Myo-inositol is a tricky compound in that its effects can be either positive or negative in different parts of the body.  In Alzheimer's disease, the three ways to increased myo-inositol production in the brain are high levels of glucose (including from a high carbohydrate diet), high levels of sodium, or Down syndrome (because people with Down syndrome have an extra chromosome carrying the gene for the sodium/myo-inositol co-transporter).  High levels of myo-inositol are a critical biomarker for the risk for the conversion of mild cognitive impairment into Alzheimer's disease.

http://www.docguide.com/myo-inositol-n-acetylaspartate-are-sensitive-biomarkers-conversion-mci-alzheimers-disease?tsid=5

Myo-inositol is converted into phosphatidylinositol 4-5 biphosphate.  If acted upon by the phosphatidyinositol 3-kinase the result is neuroprotection (a pathway cut off by presenilin gene mutations in early onset Alzheimer's disease and by peroxynitrites in late onset Alzheimer's disease). When acted upon by phospholipase C (due to the overactivation of either tyrosine receptor kinases, g protein-coupled receptors, or direct g protein activation) the result is neurodegeneration.  In particular this pathway leads to higher levels of inducible nitric oxide and peroxynitrites (and to inflammation and the formation of amyloid).

Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.

Here's a study supporting the link between ApoE4 and high myo-inositol levels in the brain. 

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(13)00476-9/abstract

Conclusions

In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased inAPOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers.

And then adding HIV to the mix: 

RESULTS:  

Frontal white matter myo-inositol was elevated in subjects with HIV across the age span but showed age-dependent increase in seronegative subjects, especially in APOE ε4+ carriers. In contrast, only seronegative APOE ε4+ subjects showed elevated myo-inositol in parietal cortex. All APOE ε4+ subjects had lower total creatine in basal ganglia. While all HIV subjects showed greater cognitive deficits, HIV+ APOE ε4+ subjects had the poorest executive function, fluency memory, and attention/working memory. Higher myo-inositol levels were associated with poorer fine motor function across all subjects, slower speed of information processing in APOE ε4+ subjects, and worse fluency in HIV+ APOE ε4+ subjects.

CONCLUSIONS:

In frontal white matter of subjects with HIV, the persistent elevation and lack of normal age-dependent increase in myo-inositol suggest that persistent glial activation attenuated the typical antagonistic pleiotropic effects of APOE ε4 on neuroinflammation. APOE ε4 negatively affects energy metabolism in brain regions rich in dopaminergic synapses. The combined effects of HIV infection and APOE ε4 may lead to greater cognitive deficits, especially in those with greater neuroinflammation. APOE ε4 allele(s) may be a useful genetic marker to identify white and mixed-race HIV subjects at risk for cognitive decline.

http://www.ncbi.nlm.nih.gov/pubmed/24850492 

Changes in levels of mI have been shown to presage the onset of cognitive decline in conditions fostering neuroinflammation, such as HIV and Alzheimer’s disease [18–21]. Elevations of mI levels in Alzheimer’s disease have been interpreted as a sign of gliosis [22]. 

http://www.hindawi.com/journals/cpn/2012/120540/ 

The above article provides a couple of explanation for how neuroinflammation might increase myo-inositol.  The  reverse is likely also true: high levels of myo-inositol increase neuroinflammation and the risk for Alzheimer's disease. 

Anyway, these biomarkers are related to inflammation which is a key early factor. This is another interesting point from your link above. Good article. Thanks for posting.

"A related explanation for increased mI/Cr in our sample is increased blood brain barrier (BBB) permeability [61], which may contribute to neuronal vulnerability and eventual cognitive decline. Myoinositol accumulates preferentially in astrocytes, which, together with endothelial tight junctions, provide selective permeability of the BBB. BBB permeability increases in the presence of inflammatory markers and may lead to toxic elevations of intracellular calcium [62]. In our sample increased levels of mI/Cr could be interpreted as an early sign of astrocyte proliferation related to impaired endothelial function and resultant osmotic stress in response to low-grade systemic inflammation."

I was looking for people in my area who study Alzheimer's disease, when I came across this interesting article on air pollution and Alzheimer's disease. This section is particularly relevant to the topic here (I just saw your chicken and egg comment, Serenoa, which is right on target). 

The effects of PM [particulate matter] on the brain are believed to be the result of two mechanisms. First, its ability to induce chronic respiratory and systemic inflammation by producing proinflammatory cytokines, which affect the blood-brain barrier, triggers neural-immune interactions and leads to chronic oxidative stress [16, 56, 75]. Second, its ability to directly produce ROS [reactive oxygen species] can damage the blood-brain barrier and increases the production of Aβ peptides [75]. Together these mechanisms are responsible for causing brain inflammation and accelerating the accumulation of Aβ peptide, both of which are associated with the neuronal dysfunction that precede the appearance of senile plaques and formation of neurofibrillary tangles [55, 74], which are the hallmarks of AD. 

http://www.hindawi.com/journals/jeph/2012/472751/ 

I am stretching it here, but it is worth a shot:

Accumulation of Myo-Inositol in Populus as a Possible Indication of Membrane Disintegration Due to Air Pollution

I have been trying to find good charts for the role of myo-inositol in Alzheimer's disease, but this is the best that I can find so far.  In a two-step process Glucose 6-phosphate is converted into myo-inositol (inositol--Ins). The next critical juncture is phophaditylinositol 4,5 biphosphate (PtdIns (4,5)P2).  When acted upon by the phosphatidylinositol 3-kinase (PI3K) it is converted into phosphatidylinositol 3,4,5 biphosphate (PtdinsP3).  This leads to the neuroprotective Akt pathway which increases blood flow in the brain, upregulation of the brain's own antioxidant system, and the regeneration of neurons in the hippocampus. When this pathway is cut off by presenilin gene mutation in early onset Alzheimer's disease or peroxynitrites in late onset Alzheimer's disease, the result is restricted blood flow in the brain, the loss of internal antioxidants, and the death of neurons.  

Chart Two.  Overactivation of g protein-coupled receptors (GPCR) or receptor tyrosine kinase receptors via phospholipase C beta or phospholipase C gamma leads to the formation of peroxynitrites (phosphatidylinositol 4,5 biphosphate--phospholipase C--diacylglycerol--protein kinase C--p38 MAPK--peroxynitrites).  Apoe4 binds to a g protein-coupled receptor (the low density lipoprotein receptor) and various viruses (HIV, herpes simplex virus 1, etc.) and bacteria (probably including lyme disease) overactivate receptor tyrosine kinases.  This leads to inflammation and oxidation and as Serenoa's research shows inflammation can increase myo-inositol levels which sets the process in motion again at least during the early stages of Alzheimer's disease.

One last chart (an old one).  The key is when you have high levels of myo-inositol (due to high levels of glucose in the brain from a diet high in sugar and carbohydrates, high sodium levels in the brain, Down syndrome, or inflammation), or when the phosphatidyinositol 3-kinase is cut off (presenilin gene mutations, bisphosphonate osteoporosis drugs such as Fosamax, and oxidative stress) or when receptor tyrosine kinases are overactivated (chronic bacterial and viral infections, high levels of glucose, traumatic brain injuries) or when g protein-coupled receptors or g proteins themselves are overactivated (the ApoE4 gene, amyloid precursor protein mutations, the c terminal fragment of the amyloid precursor protein, high fructose consumption, stress, post-traumatic stress disorder, benzodiazepines, and a host of environmental toxins including mercury, aluminum fluoride, various air pollutants, various pesticides and herbicides, and bisphenols) then your risk for developing Alzheimer's disease dramatically increase.

Lane. I just spotted a critical statement in you above post (HIV and ApoE4). 

"In frontal white matter of subjects with HIV, the persistent elevation and lack of normal age-dependent increase in myo-inositol suggest that persistent glial activation attenuated the typical antagonistic pleiotropic effects of APOE ε4 on neuroinflammation."

What does this mean? Are they saying that glial activation prevents astrocytosis in HIV patients with the ApoE4 gene? So myo-inositol is lower when HIV activates the immune system in ApoE4 carriers? This is important as it may relate to Leukine. Can you decifer anything here? Thanks.

I still need to digest all your info above.

I read the original study wrong.

Higher myo-inositol levels were associated with poorer fine motor function across all subjects, slower speed of information processing in APOE ε4+ subjects, and worse fluency in HIV+ APOE ε4+ subjects.

The persistent elevation of myo-inositol increased the neuroinflammatory effects of APOE4 in HIV patients.  Myo-inositol is converted into phosphatidylinositol 4,5 biphosphate which when acted upon by the HIV virus (via receptor tyrosine kinases) and APOE4 (via the low density lipoprotein receptor--a g protein-coupled receptor) leads to more inflammation and oxidation.

Sorry for all these charts, Serenoa, but if you put them together you largely have the answer to Alzheimer's disease.  What's missing from this chart is receptor tyrosine kinase receptors which can be activated by viruses and bacteria, high levels of glucose, oxygen and glucose deprivation, and traumatic brain injuries, and which activate phospholipase C.  The four major risk factors for Alzheimer's disease are high levels of myo-inositol (high glucose levels, high sodium levels, Down syndrome, and inflammation), inhibition of the phosphatidylinositol 3-kinase (by presenilin gene mutations for example), overactivation of receptor tyrosine kinases, and overactivation of g protein-coupled receptors (by the Apoe4 gene, stress, amyloid precursor protein mutations, environmental toxins, etc.) or direct g protein activation (c terminal fragment of the amyloid precursor protein, alumininum fluoride, sodium fluoride, etc.).

One last interesting bit about myo-inositol.  In people with Alzheimer's disease, continuing high levels of myo-inositol are connected to hallucinations.  While scyllo-inositol and lithium both reduce myo-inositol levels neither are safe treatments.  Glucuronolactones which appear to break down myo-inositol and ferulic acid which appears to bind to myo-inositol are likely better options.

Elan’s Gene Kinney recounted how falling myoinositol levels were discovered when company researchers used NMR to confirm scyllo-inositol had made its way into the brain. The researchers noticed that, as brain scyllo-inositol rose, its myo-isoform fell. Going back to animal models, they found that the myo isoform dropped by as much as 70 percent when the animals imbibed drinking water laced with scyllo-inositol. Why is this important? Previously, researchers had reported elevated brain myoinositol in patients with AD, Down's syndrome, and bipolar disorder, said Kinney (see Miller et al., 1993). More recently, a group in Japan correlated elevated brain myoinositol with behavioral and psychological problems in AD patients. Lithium, which has been used for many years to treat neuropsychiatric disorders, may work in part by reducing myoinositol. In fact, a 30 percent reduction of myoinositol is predictive of lithium efficacy, said Kinney. By reducing myoinositol, could scyllo-inositol treat neuropsychiatric symptoms in AD patients?

http://www.alzforum.org/news/conference-coverage/stockholm-therapeutics-roundup-some-new-some-not-so-much

Rather fascinating as TREM 2 variations and syk (spleen tyrosine kinase) have all been linked to Alzheimer's disease in the last year.  Granulocyte macrophage colony stimulating factor also activates the syk kinase.  The problem in Alzheimer's disease is when the right side of the chart (beginning with phospholipase C) gets overactivated and impedes the left side of the chart (phosphatidylinositol 3-kinase/Akt).

http://link.springer.com/chapter/10.1007%2F978-3-642-60419-5_26

Here is the whole trick to Alzheimer's disease.  The same kinases and receptors that can protect the brain via the phosphatidylinositol 3-kinase/Akt pathway (and Wnt and ERK) can also destroy it via phospholipase C, p38 MAPK, and peroxynitrites.  And so what appears to be beneficial can in too much quantity harm the brain (insulin is one example).  

http://www.ncbi.nlm.nih.gov/pubmed/15477536

A kinase (protein kinase C) that appears to prevent the buildup of amyloid can actually cause its build up.

http://www.jneurosci.org/content/18/8/2907.full.pdf

A kinase (AMP-activated kinase) which protects against Alzheimer's disease accelerates the progression of the disease.

http://www.ncbi.nlm.nih.gov/pubmed/21623793

In most cases what you need are receptor and kinase inhibitors (such as most polyphenols) rather than activators.

Ah yes! Here it is from 2014. I knew there was a myo-inositol Topic floating around in the archives. This is great info. I even see that you were on to the LRP/LDLr connection back then Lane.

Ok, so here is my current understanding of myo-inositol's involvement in AD. It seems to all hinge on PIP2. Myo-inositol (MI) is converted into PIP2 under normal circumstances. The problem arises when PIP2 is acted upon by PLC which eventually leads to PKC production and peroxynitrites amoung other things. We have shown why MI can be increased via inflammation, infection, high blood sugar, downs syndrome, etc. So when high MI is driving more PIP2 production the opportunity for PLC to act on PIP2 increases and leads to more PKC.

We have made the connection to cholesterol and ApoE4 as causing the activation of PLC through the LDL receptors. We have also made the connection to the benefits of PIP2 in the cell membrane, and evidence that PIP2 is deficient in AD. Therefore, if MI is creating PIP2, why is there an excess of MI in AD and a deficiency in PIP2? Or am I wrong about the amounts of PIP2 in AD?

Serenoa, I can follow your explanations regarding the pathways likely leading to Alzheimer's disease better than I can my own.

The issue of myo-inositol levels and PIP2 levels in Alzheimer's disease is a complicated one. When phospholipase C converts phosphatidyinositol 4,5 biphosphate into inositol 1,4,5 triphosphate some of IP3 is converted back into myo-inositol.  But in most people with Alzheimer's disease phospholipase C levels drop over time due to the oxidation of g protein-coupled receptors and the nitration of phospholipase C gamma.  Because of increased phospholipase C activity early in Alzheimer's disease, PIP2 deficiency occurs and because phospholipase C activity decreases later in Alzheimer's disease less IP3 and thus less myo-inositol is produced. 

But in some people with Alzheimer's disease who have hallucinations and other neuropsychiatric problems myo-inositol levels remain high.  I don't have a good explanation for this.  The one idea that I have is that stress acting through beta-adrenergic receptors (a g protein-coupled receptor) is one of the causes for neuropsychiatric problems in Alzheimer's disease.  Why every other g protein-coupled receptors is damaged in Alzheimer's disease (those affecting smell, mood, sleep, social recognition, and short-term memory) and the "stress receptor" is not is confounding. This is one possible explanation.

Adrenergic receptors in aging and Alzheimer's disease: increased beta 2-receptors in prefrontal cortex and hippocampus.

In the hippocampus, total beta- and both beta 2- and beta 1-adrenoceptors were increased in number in AD...These changes in the cortex and hippocampus suggest receptor upregulation in response to noradrenergic deafferentation from the locus ceruleus or may simply reflect glial proliferation in AD.

I found this bit of insight into PIP2, Ca2+, myo-inositol, etc. Very interesting!  What do you think Lane?

By the way I saw your posts on Science Translational Medicine. Mr. Thorson has personality issues. I liked your comment "Happy Crank Day!"

Ca2+ Influx through Store-operated Calcium Channels Replenishes the Functional Phosphatidylinositol 4,5-Bisphosphate Pool Used by Cysteinyl Leukotriene Type I Receptors

http://www.jbc.org/content/290/49/29555.short

There is a hint in the article that I am trying to fit into phosphatidylinositol 4,5 depletion.

Knockdown of talin1, a protein that helps regulate PIP5 kinases, accelerated rundown of cytoplasmic Ca2+ oscillations, and these could not be rescued by inositol or PI4P.

Calpains--an enzyme produced by the intracellular release of calcium via inositol 1,4,5 receptors--seems to activate talin which in a roundabout way helps to restore phosphatidyinositol 4, 5 levels.

Furthermore, they suggest that talin cleavage by calpain may contribute to the effects of the protease on the clustering and activation of integrins.

These findings indicate that active Beta1A integrin is required for cell migration induced by LPA (lysophosphatidyic acid) and that the cytoplasmic domain of ligated Beta1A interacts with pathways that are common to both receptor tyrosine kinase and G-protein-linked receptor signaling [and via protein kinase C to produce phosphalipase D]

It is likely that this phospholipase D2-generated phosphatidate directly stimulates phosphatidylinositol 4-phosphate 5-kinase to generate phosphatidylinositol 4,5-bisphosphate as this mechanism has previously been demonstrated in vitro.

In enzymology, a 1-phosphatidylinositol-4-phosphate 5-kinase  is an enzyme that catalyzes the chemical reaction: ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate  ADP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate

But with declining ATP production and the oxidation of g protein-coupled receptors, in most cases phosphatidyinositol 4,5 biphosphate is depleted in Alzheimer's disease.

Thanks for finding and appreciating my comment to Mark Thorson.  We have been having a running disagreement for awhile now about whether moderate to heavy smoking increases the risk for Alzheimer's disease (I think that it does).  He now just calls me a crank.  So after trying to counter some of his arguments with good quality evidence, adding "Happy Crank Day" seemed like the perfect response.

I found a good image and description for some of the above processes.

http://d2swrb3wp8hjrz.cloudfront.net/content/ajplung/284/1/L1/F2.large.jpg

Schematic representation of the phosphatidylinositol-specific phospholipase C (PI-PLC) and phospholipase D (PLD) signaling pathways. 1) PI-PLC pathway: interaction of an agonist (e.g., ATP) with an appropriate receptor (e.g., P2upurinergic receptor) leads to activation of PI-specific PLC. PI-PLC hydrolyzes phosphatidylinositol-4,5bis phosphate (PIP2), releasing inositoltris phosphate (IP3) and diacylglycerol (DAG). IP3 releases Ca2+ from intracellular stores, resulting in activation of Ca2+ calmodulin-dependent protein kinase (CM-PK). DAG activates certain PKC isoforms.2) PLD pathway: DAG-activated PKC can activate PLD. PLD hydrolyzes membrane phosphatidylcholine (PC) to phosphatidic acid (PA). The PA thus formed is degraded by lipid phosphate phosphohydrolase (LPP) to produce DAG and inorganic phosphate. DAG so produced further activates PLD, increasing the pathway, leading to a prolonged increase in PKC activation and resulting in the physiological response.

In most people as Alzheimer's disease progresses, phosphatidyinositol 4,5 biphosphate levels drop because less inositol 1,4,5 triphosphate is produced and being recycled into myo-inositol and phospholipase D activity decreases meaning less phosphatidylinositol 4,5 biphosphate is being re-produced.  

Where g protein activity remains high, phosphatidyinositol 4,5 biphosphate is likely not depelted but almost all of it is being directed toward NMDA receptor activation and the production of peroxynitrite because of the inhibition of the phosphatidyinositol 3-kinase/Akt pathway via peroxynitrite or presenilin 1-gene mutations.

http://www.ncbi.nlm.nih.gov/pubmed/16410804 

http://www.ncbi.nlm.nih.gov/pubmed/18184791

We are probably close to nailing down the pathways that lead to Alzheimer's disease.

Not sure what to make of all this. As usual, it will take me some time to digest this new info. I've been trying to make connections with varous disperate aspects of this disease lately, and Lane, you have been very helpful. I still have much to learn.

We have been talking here and in other posts about dysregulation of pathways, PIP2, LRP, LDLr, Ca2+, PLC, PKC, myo-inositol, etc., in neurons (or at least I have been thinking of them that way). What if all these things, including oxidative stress, are not themselves killing neurons? What if these things only provide signals to microglia that the neuron is stressed. And, what if the microglia are overactivated, i.e. innate immune response dysregulation, so that they misinterpret the signal and destroy the neuron? What if the adaptive immune system, which would normally regulate the innate inflammatory response of microglia, is not being activated? A convergence of factors. Yes, wild and general hypothesizing, I will post more if I actually figure out what I'm talking about.

Now to the very important question of how do neurons die in Alzheimer's disease? This one has been troubling me for years.  Here is a possible, partial explanation. Peroxynitrite does DNA damage.  That damage causes considerable energy to repair, so the cellular depletion of energy (ATP depletion) may play a role in the death of neurons.

Secondly, peroxynitrite activates caspase-3 which also leads to the death of neurons.  The following is for frontotemporal lobe dementia but it likely also applies to Alzheimer's disease.

DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia.

Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD.

The way in which caspase-3 contributes to the death of neurons is confusing for me.  I will provide a link, but in general the enzyme does all sorts of damage to proteins in the brain.

http://biology.stackexchange.com/questions/879/how-do-caspase-proteins-kill-a-cell

Peroxynitrite may trigger certain inflammatory responses while dampening others.

Dr. Grietje Krabbe of the laboratory of Professor Helmut Kettenmann (MDC) and Dr. Annett Halle of the Neuropathology Department of the Charité headed by Professor Frank Heppner demonstrated that the microglial cells around the deposits do not show the classical activation pattern in mouse models of Alzheimer´s disease. On the contrary, in the course of the Alzheimer’s disease they lose two of their biological functions. Both their ability to remove cell fragments or harmful structures and their directed process motility towards acute lesions are impaired. The impact of the latter loss-of-function needs further investigation. The plaques consist of protein fragments, the beta-amyloid peptides, which in Alzheimer’s disease are deposited in the brain over the course of years. They are believed to be involved in destroying the nerve cells of the affected patients, resulting in an incurable cognitive decline.

Peroxynitrite Inhibits T Lymphocyte Activation and Proliferation by Promoting Impairment of Tyrosine Phosphorylation and Peroxynitrite-Driven Apoptotic Death

Our results point to a physiological role for ONOO- as a down-modulator of immune responses and also as key mediator in cellular and tissue injury associated with chronic activation of the immune system.

Another possible important connection:

Protein Kinase C and Toll-Like Receptor Signaling

Thus, PKC activation is intimately involved in TLR signaling and the innate immune response.

The Toll-like receptor 4-activated neuroprotective microglia subpopulation survives via granulocyte macrophage colony-stimulating factor and JAK2/STAT5 signaling.

Toll-like receptor (TLR) 4 mediates inflammation and is also known to trigger apoptosis in microglia...Together, these results suggest that a subpopulation of TLR4-activated microglia may survive by producing GM-CSF and up-regulating GM-CSFR.

In this case, though, whether the survival of microglia is a good thing or a bad thing in regards to Alzheimer's disease is an open question.  This seems to be a biphasic process, however, initial protein kinase C activation leads to activated microglia which in turn produce peroxynitrite and which later die via peroxynitrite and caspase-3.  

I am going deeper into the morass.

Microglial activation in different stages of AD

It has been hypothesized that early microglial activation in AD delays disease progression by promoting clearance of Abeta before formation of senile plaques. It is conceivable that glial activation is protective early in the disease (Wyss-Coray et al., 2003; Maragakis and Rothstein, 2006; Wyss-Coray, 2006). In fact, studies have shown that blood derived macrophages (BMDM) are able to efficiently eliminate amyloid and confer neuroprotection by secretion of growth factors such as the glia-derived neurotrophic factor (GDNF), which are potentially beneficial to the survival of neurons (Liu and Hong, 2003). Activated microglia in early stages of AD can reduce Abeta accumulation by increasing its phagocytosis, clearance, and degradation (Frautschy et al., 1998; Qiu et al., 1998). The mechanism by which Abeta is phagocytosed depends on the physical properties of Abeta and whether it is soluble or fibrillar. Secreted Abeta1-40 and Abeta1-42 peptides are constitutively degraded by neprilysin and the insulin degrading enzyme (IDE), a metalloprotease released by microglia and other neural cells, whose enzymatic activity is enhanced by inflammatory events, such as LPS stimulation (Qiu et al., 1997).

In later stages, with persistent production of pro-inflammatory cytokines, microglia lose their protective effect (Hickman et al., 2008; Jimenez et al., 2008) and may become detrimental through the release of cytokines and chemokines (Hickman et al., 2008). These inflammatory mediators modulate immune and inflammatory function and may also alter neuronal function. In addition, microglia from old transgenic mice have a decrease in the expression of the Abeta-binding SR-A, CD36 and RAGE, and the Abeta degrading enzymes IDE, neprilysin, and matrix metalloprotease 9 (MMP9), compared with wild-type controls (Hickman et al., 2008). Therefore, all the evidences support the idea that over-activated microglia could cause uncontrolled inflammation that may drive the chronic progression of AD by exacerbating Abeta deposition and stimulating neuronal death (Mrak and Griffin, 2005; Gao and Hong, 2008). This concept constitutes the “Neuroinflammatory hypothesis.”

By comparison, the “Microglial dysfunction hypothesis” stipulates that rather than an increase of inflammatory function there is a loss of the microglial neuroprotective function in AD (Polazzi and Monti,2010). Research has shown that the phagocytic abilities of microglia are altered in aging and impaired in neurodegenerative diseases. Therefore this “senescent” or dystrophic microglia can also contribute to the onset of sporadic AD (Streit et al., 2004, 2009).

I  am advocate for the hypothesis that microglia may be slight beneficial early on by eliminating forms of amyloid that increase g protein activation (including one or more of the following: the c-terminal fragment of the amyloid precursor protein, amyloid monomers, and amyloid oligomers), but this is partially or completely offset by their role in increasing peroxynitrite.  I think microglia activation decreases as Alzheimer's disease progresses which means fewer amyloid plaques are removed (which in most cases should make little or no difference).  More importantly, microglia deactivation should mean decreased neuroinflammation as Alzheimer's disease progresses. 

Human APOE4 increases microglia reactivity at Abeta plaques in a mouse model of Abeta deposition

 http://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-11-111

Structure, expression pattern and biological activity of molecular complex TREM-2/DAP12

"TREM-2 ligation leads to the activation of Src family kinases, phosphorylation of tyrosine residues in the ITAM of DAP12, recruitment of the Syk and ZAP70 tyrosine kinases and initiation of an intracellular signaling cascade. Depending on the cell type, DAP12/TREM-2 activation plays an important role in activation and differentiation of osteoclasts, phagocytosis of bacteria, brain and bone homeostasis and inhibition of the toll-like receptor (TLR) signaling in macrophages and dendritic cells."

 http://www.ncbi.nlm.nih.gov/pubmed/23459077

For every good study I find, you find two more.  The TREM-2-src kinase connection is an important one, Serenoa.  Src activation through NMDA receptors (which in turn activate src more) leads to the formation peroxynitrite and activation of caspase 3 in Alzheimer's disease.  Another interesting clue from the article is that TREM-2 (eventually) inhibits toll like receptor signalling in macrophages and dendritic cells.  This should reduce some forms of inflammation.  You would think by this point someone would have studied whether TREM-2 also leads to the inhibition of microglia and thus also limits inflammation in middle to late Alzheimer's disease. But no such study seems to exist.

A bit closer to understanding microglia activation in Alzheimer's disease.  Microglia are activated by toll like receptors and toll like receptors are activated by protein kinase C and tyrosine phosphorylation.  The nitration of tyrosine and the decline in protein kinase C activity likely lead to a decline in toll like receptor activation as Alzheimer's disease progresses.

Granulocyte macrophage-colony stimulating factor as a PPAR agonist modulates microglia activation early in Alzheimer's disease before PPAR too is inactivated by nitration.

Microglia and Astrocyte Activation by Toll-Like Receptor Ligands: Modulation by PPAR-gamma Agonists.

Microglia and astrocytes express numerous members of the Toll-like receptor (TLR) family that are pivotal for recognizing conserved microbial motifs expressed by a wide array of pathogens...The results demonstrated differential abilities of select PPAR-gamma agonists to modulate glial activation... Collectively, this information may be exploited to modulate the host immune response during CNS infections to maximize host immunity while minimizing inappropriate bystander tissue damage that is often characteristic of such diseases.

So what likely happens is microglia activation and inflammation during the early stages of Alzheimer's disease which begins to decline as the disease continues (secondary sources of inflammation may continue to be a problem).

You said it Lane, we are definitly in the "morass." The problem is that I don't have the depth of understanding to go too deep. So when the biochemical interactions get overwhelming, I take a step back and reorient my search to the bigger picture, the general clues.

In this spirit I would like to bring the connection between thyroid and Alzheimer's (AD) into this disscusion. I have found evidence that PPARy activation is connected to having enough iodine in the diet. I have also found evidence that LRP1 is regulated by thyroid hormone, and is downregulated in hypothyroidism. And, perhaps it is relevant that thyroid hormones are tyrosine based, and can act as antioxidants. I will post the articles seperately.

Another clue is that the thyroid produces calcitonin, a molecule that regulates calcium in the blood and prevents calcium loss in the bones, and is a neurotransmitter. Therefore I ask myself, how does hypothyroid affect calcitonin levels? Apparently a known side effect of Levothoroxin (T4) is osteoporosis, which is also a common occurance with AD. My mother who has AD is also hypothyroid and has osteopenia. Coincidence?