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Plasma DYRK1A as a novel risk factor for Alzheimer's disease.

Janel N, Sarazin M, Corlier F, Corne H, de Souza LC, Hamelin L, Aka A, Lagarde J, Blehaut H, Hindié V, Rain JC, Arbones ML, Dubois B, Potier MC, Bottlaender M, Delabar JM - Transl Psychiatry (2014)

Bottom Line: In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001).DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls.These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD.

View Article: PubMed Central - PubMed

Affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, Université Paris Diderot, EAC4413 CNRS, Paris, France.

ABSTRACT
To determine whether apparent involvement of DYRK1A in Alzheimer's disease (AD) pathology makes it a candidate plasma biomarker for diagnosis, we developed a method to quantify plasma DYRK1A by immunoblot in transgenic mouse models having different gene dosages of Dyrk1a, and, consequently, different relative protein expression. Then, we measured plasma DYRK1A levels in 26 patients with biologically confirmed AD and 25 controls (negative amyloid imaging available on 13). DYRK1A was detected in transgenic mouse brain and plasma samples, and relative levels of DYRK1A correlated with the gene copy number. In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001). Results were similar when we compared AD patients with the subgroup of controls confirmed by negative amyloid imaging. In a subgroup of patients with early AD (CDR=0.5), lower DYRK1A expression was confirmed. In contrast, no difference was found in levels of DYRK1B, the closest relative of DYRK1A, between AD patients and controls. Further, AD patients exhibited a positive correlation between plasma DYRK1A levels and cerebrospinal fluid tau and phosphorylated-tau proteins, but no correlation with amyloid-β42 levels and Pittsburgh compound B cortical binding. DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls. These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD.

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DYRK1A expression in plasma as detected by immunoblot. Western blotting of (a) DYRK1A expression in mouse and human frontal cortex; and (b) DYRK1A expression in human plasma. Slot blot analysis of relative DYRK1A protein levels in: (c) cortex of Dyrk1a(+/−) mice (120-day-old males) in light grey versus wild-type mice (WT); (d) cortex of mBACtgDyrk1a mice (120-day-old males) in dark grey versus WT; (e) plasma of Dyrk1a(+/−) mice; and (f) plasma of mBACtgDyrk1a mice. Box plots indicate median with min to max, *P<0.05; a.u., arbitrary unit.
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fig1: DYRK1A expression in plasma as detected by immunoblot. Western blotting of (a) DYRK1A expression in mouse and human frontal cortex; and (b) DYRK1A expression in human plasma. Slot blot analysis of relative DYRK1A protein levels in: (c) cortex of Dyrk1a(+/−) mice (120-day-old males) in light grey versus wild-type mice (WT); (d) cortex of mBACtgDyrk1a mice (120-day-old males) in dark grey versus WT; (e) plasma of Dyrk1a(+/−) mice; and (f) plasma of mBACtgDyrk1a mice. Box plots indicate median with min to max, *P<0.05; a.u., arbitrary unit.

Mentions: To determine whether interactions with extracellular matrix proteins and other plasma proteins signalled the likely presence of DYRK1A in plasma, we performed western blotting using human albumin-depleted plasmas. Long DYRK1A isoforms migrating at the same apparent molecular weight (80–85 kDa) as the isoforms from human and mouse frontal cortex were detected using a DYRK1A mouse monoclonal antibody (Figures 1a and b) and two different rabbit DYRK1A polyclonal antibodies (data not shown), all raised against the carboxy terminus of DYRK1A.


Plasma DYRK1A as a novel risk factor for Alzheimer's disease.

Janel N, Sarazin M, Corlier F, Corne H, de Souza LC, Hamelin L, Aka A, Lagarde J, Blehaut H, Hindié V, Rain JC, Arbones ML, Dubois B, Potier MC, Bottlaender M, Delabar JM - Transl Psychiatry (2014)

DYRK1A expression in plasma as detected by immunoblot. Western blotting of (a) DYRK1A expression in mouse and human frontal cortex; and (b) DYRK1A expression in human plasma. Slot blot analysis of relative DYRK1A protein levels in: (c) cortex of Dyrk1a(+/−) mice (120-day-old males) in light grey versus wild-type mice (WT); (d) cortex of mBACtgDyrk1a mice (120-day-old males) in dark grey versus WT; (e) plasma of Dyrk1a(+/−) mice; and (f) plasma of mBACtgDyrk1a mice. Box plots indicate median with min to max, *P<0.05; a.u., arbitrary unit.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150238&req=5

fig1: DYRK1A expression in plasma as detected by immunoblot. Western blotting of (a) DYRK1A expression in mouse and human frontal cortex; and (b) DYRK1A expression in human plasma. Slot blot analysis of relative DYRK1A protein levels in: (c) cortex of Dyrk1a(+/−) mice (120-day-old males) in light grey versus wild-type mice (WT); (d) cortex of mBACtgDyrk1a mice (120-day-old males) in dark grey versus WT; (e) plasma of Dyrk1a(+/−) mice; and (f) plasma of mBACtgDyrk1a mice. Box plots indicate median with min to max, *P<0.05; a.u., arbitrary unit.
Mentions: To determine whether interactions with extracellular matrix proteins and other plasma proteins signalled the likely presence of DYRK1A in plasma, we performed western blotting using human albumin-depleted plasmas. Long DYRK1A isoforms migrating at the same apparent molecular weight (80–85 kDa) as the isoforms from human and mouse frontal cortex were detected using a DYRK1A mouse monoclonal antibody (Figures 1a and b) and two different rabbit DYRK1A polyclonal antibodies (data not shown), all raised against the carboxy terminus of DYRK1A.

Bottom Line: In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001).DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls.These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD.

View Article: PubMed Central - PubMed

Affiliation: Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, Université Paris Diderot, EAC4413 CNRS, Paris, France.

ABSTRACT
To determine whether apparent involvement of DYRK1A in Alzheimer's disease (AD) pathology makes it a candidate plasma biomarker for diagnosis, we developed a method to quantify plasma DYRK1A by immunoblot in transgenic mouse models having different gene dosages of Dyrk1a, and, consequently, different relative protein expression. Then, we measured plasma DYRK1A levels in 26 patients with biologically confirmed AD and 25 controls (negative amyloid imaging available on 13). DYRK1A was detected in transgenic mouse brain and plasma samples, and relative levels of DYRK1A correlated with the gene copy number. In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001). Results were similar when we compared AD patients with the subgroup of controls confirmed by negative amyloid imaging. In a subgroup of patients with early AD (CDR=0.5), lower DYRK1A expression was confirmed. In contrast, no difference was found in levels of DYRK1B, the closest relative of DYRK1A, between AD patients and controls. Further, AD patients exhibited a positive correlation between plasma DYRK1A levels and cerebrospinal fluid tau and phosphorylated-tau proteins, but no correlation with amyloid-β42 levels and Pittsburgh compound B cortical binding. DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls. These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD.

Show MeSH
Related in: MedlinePlus