Journal of neurochemistryNov 17, 2007

Phosphorylation of amyloid precursor protein by a key enzyme may link Down syndrome and Alzheimer's disease

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Updated Mar 29, 2026

Abstract

Individuals with Down Syndrome may have increased levels of phosphorylated APP and beta-amyloid in their brains.

An extra copy of a segment of chromosome 21 in Down Syndrome is linked to early-onset Alzheimer's disease.
DYRK1A, a protein kinase located on chromosome 21, phosphorylates the beta-amyloid precursor protein (APP) at a specific site (Thr668).
In transgenic mice over-expressing DYRK1A, levels of phosphorylated APP and beta-amyloid are elevated.
Human brains from individuals with Down Syndrome also show increased levels of phosphorylated APP, APP, and DYRK1A.
These findings suggest a regulatory connection between DYRK1A and APP that could influence Alzheimer's disease progression in Down Syndrome.

Simplified

Most individuals with Down Syndrome (DS) show an early-onset of Alzheimer's disease (AD), which potentially results from the presence of an extra copy of a segment of chromosome 21. Located on chromosome 21 are the genes that encode beta-amyloid (Abeta) precursor protein (APP ), a key protein involved in the pathogenesis of AD, and dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A (DYRK1A ), a proline-directed protein kinase that plays a critical role in neurodevelopment. Here, we describe a potential mechanism for the regulation of AD pathology in DS brains by DYRK1A-mediated phosphorylation of APP. We show that APP is phosphorylated at Thr668 by DYRK1A in vitro and in mammalian cells. The amounts of phospho-APP and Abeta are increased in the brains of transgenic mice that over-express the human DYRK1A protein. Furthermore, we show that the amounts of phospho-APP as well as those of APP and DYRK1A are elevated in human DS brains. Taken together, these results reveal a potential regulatory link between APP and DYRK1A in DS brains, and suggest that the over-expression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.

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Phosphorylation of amyloid precursor protein by a key enzyme may link Down syndrome and Alzheimer's disease

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