Protective amyloid precursor protein (APP) mutation lowers Aβ in blood

More support for amyloid hypothesis

Five years ago, Icelandic scientists found a mutation in the amyloid precursor protein (APP) that protected carriers against developing Alzheimer’s disease, ostensibly by decreasing production of amyloid-beta (Aβ) peptides. Now, researchers at the University of Eastern Finland in Kuopio show that Finnish men with the protective mutation A673T have on average 28 percent less plasma Aβ than those without the gene. The results appeared in the Annals of Neurology online on May 26.

Christian Haass of the German Center of Neurodegenerative Diseases in Munich: “It really shows what these protective mutations are doing: they reduce amyloid production over the lifetime and prevent the disease.” Haass said the work provides clear support for the amyloid-cascade hypothesis of AD, which puts amyloid production at the head of a pathological sequence of events leading to disease. The work also suggests a path to prevention, indicating that a less-than-total blockade of Aβ production, if maintained through life, yields benefits later on.


Evidence for decreased plasma Aβ
The Finnish group is the first to publish evidence for decreased plasma Aβ in A673T carriers, but Kári Stefánsson of deCODE Genetics, Reykjavik, Iceland, told his group has similar, unpublished results. Their data on about 200 mutation carriers shows a 15 percent reduction in plasma Aβ, Stefánsson said. “This result is real and it is significant.”

Stefánsson’s deCODE team was the first to identify the salubrious effects of the APP A673T mutation, which protects carriers from AD and age-related cognitive decline. The mutation renders APP resistant to β-secretase (BACE) cleavage, and lowers Aβ output from neurons in vitro. The mutation appears in a lucky few in Iceland and Scandinavia, but is practically missing from other parts of the world.



Source:  Alzforum |  June 15, 2017

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