Curcumin restores innate immune Alzheimer's disease risk gene expression to ameliorate Alzheimer pathogenesis

[BrianR]

Paywalled: https://www.sciencedirect.com/science/a ... 6119300452
Neurobiology of Disease. Volume 127, July 2019, Pages 432-448
B. Teter, T. Morihara, G.P. Lim, T. Chu, M.R. Jones, X. Zuo, R.M., Paul, S.A. Frautschy, G.M. Cole
DOI: 10.1016/j.nbd.2019.02.015

Their work seems to have been done in a live mouse model and with human & mouse microglial cells in vitro. It's not clear to me what implications their dosing may have for those of us taking curcumin capsules.

They go into significant detail regarding the process by which they believe curcumin helps Aβ clearance. If you're interested in that level of detail and can get access to the paper, you may find it worthwhile.

Highlights

• Curcumin (Curc) restores innate immune gene expression in AD models.
• Curc increased TREM2 and TYROBP, while decreasing CD33 expression.
• Curc stimulates phagocytosis and increases CD68 and Arg1 expression.
• Curc reduces pro-inflammatory microglia markers CD11b, iNOS, COX-2, IL1β.
• These results support a novel mechanism for Curc, which emulates the Aβ vaccine.

Abstract
Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 [amounts] (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β).

In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships.

Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2.

Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo.

We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.

from the body of the paper, regarding dosage:

The effects of different doses of diet-administered curcumin, low dose (160 ppm, “Curc-Lo”) and 30-fold higher dose (5,000 ppm, “Curc-Hi”), on microglial activation and [amount] of AD genetic risk factor microglial genes were evaluated in APPSwe (Tg2576) transgenic amyloid plaque-forming mice. Tg2576 mice were fed curcumin doses of 0, 160 or 5,000 ppm in PMI 5015 breeder chow from 10 to 16 months of age.

We previously reported that these Curc-Lo-treated mice showed decreased inflammation and oxidative damage (e.g. decreased IL1β, GFAP and carbonyl (oxidized) proteins) as well as decreased Aβ levels (decreased amyloid plaque burden, soluble Aβ, and insoluble Aβ) in the brain (Lim et al., 2001). While using an intermediate dosing with 500 ppm from 17 to 22 months (after amyloid accumulation) produced large decreases in IL1β and amyloid burden (Yang et al., 2005), surprisingly, Curc-Hi did not affect insoluble or soluble Aβ levels (Lim et al., 2001),

[mike]

Interesting that the higher dose did not seem to have an effect...wonder why? Need to figure out top of the curve for max human effectiveness

[SusanJ]

My best guess is that curcumin is an antioxidant. Take too much of any antioxidant and you are messing with important signaling mechanisms when it comes to the immune system. And antioxidants are cumulative, so if you take others besides curcumin, you might get to that point of no effect more quickly. There are also some genetic issues at play, too. I did a quick post a while back at viewtopic.php?f=4&t=2121&p=24075&hilit=ROS#p24075

[aphorist]

My guess is that based on the work at the Salk Institute (J147, etc.) that curcumin elicits a retrograde mitochondrial response by inhibiting ATP synthase, the last step in ATP formation in the mitochondria. It is only an antioxidant to the extent it upregulates endogenous production of antioxidant enzymes like SOD2, glutathione, etc., which I think would be different than administration of something like NAC.

I think a question would be how metformin/berberine (a purported Complex I mitochondrial inhibitor) might see additive or excessive effects with curcumin.

https://onlinelibrary.wiley.com/doi/ful ... acel.12715

https://www.technologynetworks.com/neur ... ers-296115

Fully understanding the mitochondrial retrograde response of lowered ATP and how curcumin is working here has long been on my to-do list, if anyone can write a brief synopsis

[circular]

My guess is that based on the work at the Salk Institute (J147, etc.) that curcumin elicits a retrograde mitochondrial response by inhibiting ATP synthase, the last step in ATP formation in the mitochondria.

Is this to say that curcumin potentially diminishes the energy producing capacity of the mitochondria? Cripes, I need more energy, not less, and I've taken it for years. Hopefully it's just a tiny effect at the margins, or most likely, waaaaaaaay more complicated?

[aphorist]

Is this to say that curcumin potentially diminishes the energy producing capacity of the mitochondria? Cripes, I need more energy, not less, and I've taken it for years. Hopefully it's just a tiny effect at the margins, or most likely, waaaaaaaay more complicated?

I don't know the answer to that exactly. Because while each individual mitochondria might have a diminished ATP output, there (likely) could be a response whereby there is mitochondrial fission and an increase in overall density, with a concomitant of higher antioxidant enzymes in each mitochondria to deal with higher levels of ROS, such that each mitochondria was more metabolically efficient, but lower in its output.

I'm just theorizing. I don't really know the answer.

[sarahb12]

curcumin also reduces the expression of PAI-1

[circular]

Interesting that the higher dose did not seem to have an effect...wonder why? Need to figure out top of the curve for max human effectiveness

Can anyone do this? Not that it would be evidence-based in humans, but I'd sure like to know: if the results translate to humans, what would be our optimal does. As Susan suggests, it may depend on our overall antioxidant status. Any of us taking curcumin must be either wasting our money by taking too much, wasting our money by not taking enough, or hitting it just right. Seems we need a validated lab for curcumin status to measure our individual stores vs amount of supplementation. Absent any science to guide me, maybe based on my thin phenotype I can reduce my twice a day Theracurmin to once a day and save a little $.

[mike]

Absent any science to guide me, maybe based on my thin phenotype I can reduce my twice a day Theracurmin to once a day and save a little $.

my guess is that it will be somewhat individual. You will need to find your own sweet spot. Try a smaller dose and see if you notice a difference...

[BrianR]

Absent any science to guide me, maybe based on my thin phenotype I can reduce my twice a day Theracurmin to once a day and save a little $.

my guess is that it will be somewhat individual. You will need to find your own sweet spot. Try a smaller dose and see if you notice a difference...

If I remember correctly, the Theracurmin study found that patients needed to take the dosage (180mg/day iirc) for 18 months to see results in the brain. (That is, even in Theracurmin formulation, curcumin only slowly crosses the blood-brain barrier and those requires extended usage to attain effective concentrations.)

Thus, with the long delays in effect, I'd guess that varying what you take based on how you perceive it working in your brain probably won't work well. Of course, if it has other effects in your body, you may be able to effectively titrate the dosage.

(I happen to use Theracurmin, hoping that the money spent will provide value. But, like a lot of supplements/drugs, it's just another bit of faith-based, evidence lacking [in my body] medicine.)