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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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DYRK1 protein levels in plasma from control (CTRL) individuals and Alzheimer's disease (AD) patients. Slot-blotting was used to detect relative expression of (a) DYRK1A in CTRL and AD; (b) DYRK1B in CTRL and AD; (c) DYRK1A in CTRL and early-stage AD. White dots: controls; black dots: AD patients. Graph bars indicate mean±s.e.m; ****P<0.0001; ***P<0.001; a.u., arbitrary unit.
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fig2: DYRK1 protein levels in plasma from control (CTRL) individuals and Alzheimer's disease (AD) patients. Slot-blotting was used to detect relative expression of (a) DYRK1A in CTRL and AD; (b) DYRK1B in CTRL and AD; (c) DYRK1A in CTRL and early-stage AD. White dots: controls; black dots: AD patients. Graph bars indicate mean±s.e.m; ****P<0.0001; ***P<0.001; a.u., arbitrary unit.

Mentions: Using the same method as in mouse, we detected DYRK1A in human plasma. Mean relative DYRK1A expression was significantly lower in AD patients as compared with controls (P<0.0001; Figure 2a). As a control, we assessed expression of DYRK1B (or MIRK), a member of the same kinase family as DYRK1A, which presents a different pattern of expression and is expressed at low levels in the brain.19 This protein has been detected previously in plasma (plasma protein database). Plasma samples from a subgroup of CTRL and AD patients were analysed with the same slot blot method. Relative DYRK1B expression was similar between groups (Figure 2b). Further, in the subgroup of patients with early AD (CDR=0.5), the same decrease in DYRK1A expression was found (Figure 2c). When we compared DYRK1A levels between AD patients and controls for whom PiB-PET imaging was available (n=17 AD patients with positive amyloid imaging and n=13 controls with negative amyloid imaging), we observed similar results (Figure 3a). No difference was found in plasma DYRK1A levels in AD patients at an early stage (CDR=0.5) and AD patients at a dementia stage (CDR⩾1). DYRK1A protein levels were not correlated with the Mini-Mental State Exam scores.


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)

DYRK1 protein levels in plasma from control (CTRL) individuals and Alzheimer's disease (AD) patients. Slot-blotting was used to detect relative expression of (a) DYRK1A in CTRL and AD; (b) DYRK1B in CTRL and AD; (c) DYRK1A in CTRL and early-stage AD. White dots: controls; black dots: AD patients. Graph bars indicate mean±s.e.m; ****P<0.0001; ***P<0.001; a.u., arbitrary unit.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: DYRK1 protein levels in plasma from control (CTRL) individuals and Alzheimer's disease (AD) patients. Slot-blotting was used to detect relative expression of (a) DYRK1A in CTRL and AD; (b) DYRK1B in CTRL and AD; (c) DYRK1A in CTRL and early-stage AD. White dots: controls; black dots: AD patients. Graph bars indicate mean±s.e.m; ****P<0.0001; ***P<0.001; a.u., arbitrary unit.
Mentions: Using the same method as in mouse, we detected DYRK1A in human plasma. Mean relative DYRK1A expression was significantly lower in AD patients as compared with controls (P<0.0001; Figure 2a). As a control, we assessed expression of DYRK1B (or MIRK), a member of the same kinase family as DYRK1A, which presents a different pattern of expression and is expressed at low levels in the brain.19 This protein has been detected previously in plasma (plasma protein database). Plasma samples from a subgroup of CTRL and AD patients were analysed with the same slot blot method. Relative DYRK1B expression was similar between groups (Figure 2b). Further, in the subgroup of patients with early AD (CDR=0.5), the same decrease in DYRK1A expression was found (Figure 2c). When we compared DYRK1A levels between AD patients and controls for whom PiB-PET imaging was available (n=17 AD patients with positive amyloid imaging and n=13 controls with negative amyloid imaging), we observed similar results (Figure 3a). No difference was found in plasma DYRK1A levels in AD patients at an early stage (CDR=0.5) and AD patients at a dementia stage (CDR⩾1). DYRK1A protein levels were not correlated with the Mini-Mental State Exam scores.

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