The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease

Abstract

We scanned throughout chromosome 21 to assess genetic associations with late-onset Alzheimer disease (AD) using 374 Japanese patients and 375 population-based controls, because trisomy 21 is known to be associated with early deposition of beta-amyloid (Abeta) in the brain. Among 417 markers spanning 33 Mb, 22 markers showed associations with either the allele or the genotype frequency (P < 0.05). Logistic regression analysis with age, sex and apolipoprotein E (APOE)-epsilon4 dose supported genetic risk of 17 markers, of which eight markers were linked to the SAMSN1, PRSS7, NCAM2, RUNX1, DYRK1A and KCNJ6 genes. In logistic regression, the DYRK1A (dual-specificity tyrosine-regulated kinase 1A) gene, located in the Down syndrome critical region, showed the highest significance [OR = 2.99 (95% CI: 1.72-5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR = 23.3 (95% CI: 2.76-196.5), P = 0.038]. DYRK1A mRNA level in the hippocampus was significantly elevated in patients with AD when compared with pathological controls (P < 0.01). DYRK1A mRNA level was upregulated along with an increase in the Abeta-level in the brain of transgenic mice, overproducing Abeta at 9 months of age. In neuroblastoma cells, Abeta induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr212 under the overexpression of tau. Therefore, the upregulation of DYRK1A transcription results from Abeta loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between beta-amyloid production and tau phosphorylation in AD.

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier

“…The AD cases were recruited from Osaka University Hospital (44,45) and met the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for probable AD. The control cases were recruited from healthy elderly volunteers with no history of dementia or other neuropsychiatric diseases (44,45). The purpose and significance of the present study were explained in detail to each patient and his/ her family, and all subjects provided their informed consent.…”

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

“…DYRK1A mRNA and Aβ levels in the hippocampus are higher in patients with AD, transgenic mice and neuroblastoma cells (Kimura et al, 2007). In addition, Aβ induces an increase in the DYRK1A transcript, which leads to tau phosphorylation and overexpression of tau (Kimura et al, 2007).…”

“…DYRK1A mRNA and Aβ levels in the hippocampus are higher in patients with AD, transgenic mice and neuroblastoma cells (Kimura et al, 2007). In addition, Aβ induces an increase in the DYRK1A transcript, which leads to tau phosphorylation and overexpression of tau (Kimura et al, 2007). Thus, the upregulation of DYRK1A transcription resulting from Aβ overload further leads to tau phosphorylation, suggesting that DYRK1A could be a key molecule bridging β-amyloid production and tau phosphorylation in AD.…”

“…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.…”

“…However, several studies in transgenic mice in which only the Dyrk1A gene is overexpressed or in trisomic mice that do not carry an extra functional copy of APP show tau pathology (Sheppard et al 2012;Kimura et al, 2007). Thus, the enhanced phosphorylation observed in these models occurs independently of an extra copy of this gene, indicating that the activity of DYRK1A and other kinases may not need to interact with APP or Aβ to induce this hyperphosphorylation.…”