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

Abstract

Caused by the presence of an extra copy of human chromosome 21 (trisomy 21), Down syndrome (DS) is the most common genetic disorder with an incidence of one in 800 live births. DS patients suffer various symptoms, including mental retardation and an early-onset of Alzheimer's disease (AD). The brains of both DS and AD patients show increased amounts of b-amyloid (Ab), which leads to the formation of amyloid plaques, a hallmark of AD pathogenesis (Mann and Esiri 1989). Although the cause of an early-onset AD in DS patients is not clearly understood (Wisniewski et al. 1985), one potential mechanism is overexpression of the gene for b-amyloid precursor protein (APP) located on chromosome 21. Three copies of the APP gene are necessary for DS-affected individuals to develop AD pathology (Prasher et al. 1998). However, this genetic background does not sufficiently account for the full spectrum of pathologies seen in AD patients; over-expres- Abbreviations used: aa, amino acids; AD, Alzheimer's disease; APP, amyloid precursor protein; APPct, C-terminal fragment of APP; Ab, b-amyloid; BACE1, b-secretase APP Cleaving Enzyme 1; DS, Down syndrome; DYRK1A, dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A; GFP, green fluorescent protein; GST, glutathione S-transferase; NGF, nerve growth factor; p-AICD, phospho-APP intracellular domain; PBS, phosphate-buffered saline; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TG, transgenic; WT, wild-type; YF, Y321F kinase-inactive mutant. AbstractMost individuals with Down Syndrome (DS) show an earlyonset 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 b-amyloid (Ab) 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 Ab 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 overexpression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.

Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A) Modulates Serine/Arginine-rich Protein 55 (SRp55)-promoted Tau Exon 10 Inclusion

“…Mutation of Ser-303 to Ala, but not Ser-280 and Ser-316, increased the promotion of SRp55 in Tau exon 10 inclusion. In addition, it is known that in addition to the consensus sites, Dyrk1A also phosphorylates Ser/Thr within non-consensus site (42)(43)(44)(45). The RS domain of SRp55 has many Ser/Thr resides that probably are phosphorylated by Dyrk1A with low efficiency.…”

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

“…A possible mechanism that has been proposed to account for the interplay between DYRK1A and APP is a positive feedback loop (see Cardenas et al, 2012) in which DYRK1A phosphorylates APP at Thr668 (Ryoo et al, 2008) favoring the amyloidogenic cleavage of APP (Judge et al, 2011;Lee et al, 2003), and Aβ42 induces an upregulation of DYRK1A (Kimura et al, 2007). The cooperative effects of these genes could affect tau expression and phosphorylation and result in abnormal expression and hyperphosphorylation, favouring tau aggregation and the destabilization of microtubules.…”

“…Although the extra copy of APP and its overexpression seems to be the primary cause of amyloidosis in the DS brain, several studies have demonstrated that DYRK1A plays an important role in this process by interacting with APP. DYRK1A phosphorylates APP at Thr668 in vitro in cells of a mouse model that overexpresses the human DYRK1A gene (hBACtgDyrk1A) (Ryoo et al, 2008). This phosphorylation facilitates the excision of APP by β-secretase 1 (Beta-secretase 1, BACE1) and γ-secretase, inducing an accumulation of the neurotoxic peptides Aβ40 and Aβ42 (Wegiel et al, 2011;Vingtdeux et al, 2005;Lee et al, 2003).…”

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

“…For example, the transcription factor ETS2 is thought to transactivate the APP promoter, leading to overexpression 123 . The chromosome 21-encoded proteins small ubiquitin-related modifier 3 (SUMO3) and dualspecificity tyrosinephosphorylation-regulated kinase 1A (DYRK1A) modify APP posttranslationally, which may alter Aβ generation [124][125][126] . Additionally, the chromosome 21 microRNA miR-155 has been suggested to modulate γ-secretase activity and hence the processing of APP, through its effect on the expression of sorting nexin 27 (REF.…”