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Thursday, January 27, 2011

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)

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