Review Again and Again and Again

Whew!! These blogs have been a lot of science. If you are still with me, let's review.
3 Players:
These genes are at a triple dose in Down syndrome:

1. DYRK1A
2. RCAN or (DSCR1)
3. APP

DYRK1A is triplicated (3X) in Down Syndrome and is involved in cell growth and development.

• decrease brain volume (slows cell growth and development)
• decreases synaptic plasticity [decreases BDNF (Brain Derived Neurotrophic Factor)- like brain food]
• increases the production of the toxic amyloid beta plaque
• hyperphosphoralates tau protein which is a structural protein inside the nerves. The tau protein falls off the internal structure leading to collapse of the nerve

RCAN or (DSCR1)

• decreases cell growth and therefore brain volume
• the DSCR stands for Down Syndrome Critical Region. It has since been renamed to RCAN

APP stands for Amyloid Precursor Protein

• 3 enzymes cut this protein in different spots
•  the DYRK1A changes the APP and sets it up to be cut in a toxic manner creating the poisonous amyloid beta plaque.
• The amyloid beta plaque is hallmark of Alzheimer's and Down syndrome brain pathology
• in a mouse model, 3 times APP alone does not show the same pathological changes seen in Down syndrome
• in a mouse model, 3 times APP and 3 times DYRK1A does resemble the brain changes seen in Down syndrome. Also, these mice have similar learning deficiencies seen in Down syndrome.

What can we do to help turn down these genes? Well obviously we need to rebalance the system if we can.

One thing came up over and over in the journal articles. GREEN TEA EXTRACT

Green Tea Extract decreases the expression of the DYRK1A gene.

So, if DYRK1A was expressed at a more normal level, the person with Down syndrome should be able to grow nerve cells and therefore normalize brain volume. Learning and memory should increase with more synaptic plasticity. Forming less amyloid beta plaques should at least delay the onset of toxic plaque build up in the brain. And, structurally, the tau protein should stay more normal therefore, less nerve cells will collapse.

Another journal article, found that ANTIDEPRESSANTS decrease the expression of the RCAN gene. There were some contradictory studies on this point but ANTIDEPRESSANTS also are known to increase BDNF which is probably a good thing in Down syndrome.

Thanks for the comments on facebook. I know this is tough stuff but you don't have to know every detail. You need to understand the overall pathology that is an ongoing problem in Down syndrome. 'WE CAN' help our loved ones with Down syndrome. It is like an onion one layer at a time.

Could the DYRK1A gene increase Amyloid Plaques?

In the last post, we talked about the amyloid plaque and how it gunks up the works (ie. brain). Just to review, Down syndrome have 3 copies of the APP gene, which stands for amyloid precursor protein. But their is a twist to the story, "over-expression of APP alone in mice does not cause the AD-like (Alzheimer Disease - like) [endosome] pathology observed in DS patients."  So just having 3 copies of the APP gene does not create the biological disease state that is seen in Down syndrome, mice and people.

So, the next question is what else contributes to the formation of amyloid plaques and therefore, a disease state?

We are back to our friendly DYRK1A gene. Having 3 copies of DYRK1A plus 3 copies of APP creates the perfect storm that does result in the pathology seen in patients with Down syndrome. Another link in the chain.

{We need a big white board to keep track of all the connections.}

OK back to the science:

Let's look at how DYRK1A affects APP.

"DYRK1A and APP give rise to AD pathology in DS brains through

DYRK1A-mediated phosphorylation of APP." (1)

Phosphorylation means to activate or deactivate protein enzymes

"The over-expression of DYRK1A in DS brains may accelerate the development of

AD pathogenesis through phosphorylation of the Thr668 residue of APP, a

modification that may be necessary for the APP cleavage events that give rise to Aβ (amyloid beta plaque)."(1)
Let's review :

• The brain chemistry in Down syndrome is producing the toxic amyloid plaques at a higher rate than normal.
• A mouse model with only triple APP does not show the same pathology as seen in Down syndrome.
• A mouse model with only triple DYRK1A does show learning and memory deficiencies similar to Down syndrome.
• A mouse model with a triple APP and DYRK1A show the same pathology seen in human Down syndrome brains.

At the end of the study cited above, they say, "therapeutics that inhibit DYRK1A expression and/or kinase activity might suppress the early-onset of AD and mental retardation in DS patients." (1)
A few potent DYRK1A inhibitors have been described but the one that keeps popping up in these journal articles is epigallocatechin 3-gallate (EGCG), in other words, green tea extract.
We will continue this scientific avenue looking at tau protein (strucural component inside nerves) next. Review the video in previous post.

Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease  (1)

Benefits of Curcumin for Down syndrome

I finally had a chance to research curcumin and I am delightfully surprised. It has some properties similar to prozac but it has even more. One research study I found looked at curcumin using what is called an 'unpredictable stress model'.  This is when the researchers stress the mice in random, unpredictable ways. They have found this to be the most stressful on the mice.  If stress is consistent and/or predictable, it is not as hard on the body or brain.



Curcumin did increase neurogenesis by increasing serotonin and BDNF (brain derived neurotrophic factor). But it did something more that I think may be the biggest help to Down syndrome.


Curcumin is an anti-inflammatory as well as an antioxidant, but that is not the most intriguing part of the research. Lots of herbs and vitamins are anti-inflammatory or have antioxidant properties.


The most intriguing part is the idea that curcumin is structurally capable of binding to amyloid plaques and breaking up the aggregation of them. Curcumin literally sticks itself to the junk (amyloid plaque) and breaks up the group of them stuck together.


This group of junk clogs up the brain and stops it from working.


Down syndrome has a triplicate copy of the APP gene. Amyloid precursor protein gene. This is the gene associated with Alzheimer's disease. In Alzheimer's disease, brain researchers find the brains full of plaques and tangles. The plaques are called amyloid plaques.


Now, the big drawback I see to curcumin is getting it into the brain. It doesn't cross the BBB (blood brain barrier) easily. But, one brand, Longvida Curcumin, came up with an intriguing solution. They combined curcumin with lecithin. What does that do, you ask? Well, lecithin is phosphatidyl choline, a fat that will cross the BBB. Brilliant!!!



I think curcumin is a fantastic addition for the health of the Down syndrome brain (and probably everyone would benefit).