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f143dd514338c4deb349947020ed4a31903adfd45d97f438a6f7e13fb6503aa4  pmc_9219646.pdf

Title:          DYRK1A and Activity-Dependent Neuroprotective Protein Comparative Diagnosis Interest in Cerebrospinal Fluid and Plasma in the Context of Alzheimer-Related Cognitive Impairment in Down Syndrome Patients
Subject:        Down syndrome (DS) is a complex genetic condition due to an additional copy of human chromosome 21, which results in the deregulation of many genes. In addition to the intellectual disability associated with DS, adults with DS also have an ultrahigh risk of developing early onset Alzheimer’s disease dementia. DYRK1A, a proline-directed serine/threonine kinase, whose gene is located on chromosome 21, has recently emerged as a promising plasma biomarker in patients with sporadic Alzheimer’s disease (AD). The protein DYRK1A is truncated in symptomatic AD, the increased truncated form being associated with a decrease in the level of full-length form. Activity-dependent neuroprotective protein (ADNP), a key protein for the brain development, has been demonstrated to be a useful marker for symptomatic AD and disease progression. In this study, we evaluated DYRK1A and ADNP in CSF and plasma of adults with DS and explored the relationship between these proteins. We used mice models to evaluate the effect of DYRK1A overexpression on ADNP levels and then performed a dual-center cross-sectional human study in adults with DS in Barcelona (Spain) and Paris (France). Both cohorts included adults with DS at different stages of the continuum of AD: asymptomatic AD (aDS), prodromal AD (pDS), and AD dementia (dDS). Non-trisomic controls and patients with sporadic AD dementia were included for comparison. Full-form levels of DYRK1A were decreased in plasma and CSF in adults with DS and symptomatic AD (pDS and dDS) compared to aDS, and in patients with sporadic AD compared to controls. On the contrary, the truncated form of DYRK1A was found to increase both in CSF and plasma in adults with DS and symptomatic AD and in patients with sporadic AD with respect to aDS and controls. ADNP levels showed a more complex structure. ADNP levels increased in aDS groups vs. controls, in agreement with the increase in levels found in the brains of mice overexpressing DYRK1A. However, symptomatic individuals had lower levels than aDS individuals. Our results show that the comparison between full-length and truncated-form levels of DYRK1A coupled with ADNP levels could be used in trials targeting pathophysiological mechanisms of dementia in individuals with DS.
Keywords:       Down syndrome; Alzheimer’s disease; DYRK1A; ADNP; brain; plasma; CSF
Author:         Manon Moreau, Maria Carmona-Iragui, Miren Altuna, Lorraine Dalzon, Isabel Barroeta, Marie Vilaire, Sophie Durand, Juan Fortea, Anne-Sophie Rebillat and Nathalie Janel
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        Title: ADNP Protein Level Is Linked to DYRK1A Protein Level in the Mouse Brain 
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       Item: 
        Title: DYRK1A Protein Level Is Modified in LCLs from DS Patients with AD Dementia 
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        Title: DYRK1A Protein Level Is Modified in CSF and Plasma in DSAD 
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        Title: DYRK1A Protein Level Is Modified in CSF and Plasma from Sporadic AD Patients 
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    Title: DYRK1A and Activity-Dependent Neuroprotective Protein Comparative Diagnosis Interest in Cerebrospinal Fluid and Plasma in the Context of Alzheimer-Related Cognitive Impairment in Down Syndrome Patients
    Author: Manon Moreau, Maria Carmona-Iragui, Miren Altuna, Lorraine Dalzon, Isabel Barroeta, Marie Vilaire, Sophie Durand, Juan Fortea, Anne-Sophie Rebillat and Nathalie Janel
    Subject: Down syndrome (DS) is a complex genetic condition due to an additional copy of human chromosome 21, which results in the deregulation of many genes. In addition to the intellectual disability associated with DS, adults with DS also have an ultrahigh risk of developing early onset Alzheimer’s disease dementia. DYRK1A, a proline-directed serine/threonine kinase, whose gene is located on chromosome 21, has recently emerged as a promising plasma biomarker in patients with sporadic Alzheimer’s disease (AD). The protein DYRK1A is truncated in symptomatic AD, the increased truncated form being associated with a decrease in the level of full-length form. Activity-dependent neuroprotective protein (ADNP), a key protein for the brain development, has been demonstrated to be a useful marker for symptomatic AD and disease progression. In this study, we evaluated DYRK1A and ADNP in CSF and plasma of adults with DS and explored the relationship between these proteins. We used mice models to evaluate the effect of DYRK1A overexpression on ADNP levels and then performed a dual-center cross-sectional human study in adults with DS in Barcelona (Spain) and Paris (France). Both cohorts included adults with DS at different stages of the continuum of AD: asymptomatic AD (aDS), prodromal AD (pDS), and AD dementia (dDS). Non-trisomic controls and patients with sporadic AD dementia were included for comparison. Full-form levels of DYRK1A were decreased in plasma and CSF in adults with DS and symptomatic AD (pDS and dDS) compared to aDS, and in patients with sporadic AD compared to controls. On the contrary, the truncated form of DYRK1A was found to increase both in CSF and plasma in adults with DS and symptomatic AD and in patients with sporadic AD with respect to aDS and controls. ADNP levels showed a more complex structure. ADNP levels increased in aDS groups vs. controls, in agreement with the increase in levels found in the brains of mice overexpressing DYRK1A. However, symptomatic individuals had lower levels than aDS individuals. Our results show that the comparison between full-length and truncated-form levels of DYRK1A coupled with ADNP levels could be used in trials targeting pathophysiological mechanisms of dementia in individuals with DS.
    Keywords: Down syndrome; Alzheimer’s disease; DYRK1A; ADNP; brain; plasma; CSF
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       Subtype: Link
       Rect: 59, 550, 96, 560
      Annotation: 
       Subtype: Link
       Rect: 109, 515, 146, 525
      Annotation: 
       Subtype: Link
       Rect: 153, 515, 189, 525
      Annotation: 
       Subtype: Link
       Rect: 229, 481, 267, 491
      Annotation: 
       Subtype: Link
       Rect: 273, 481, 309, 491
  Checksum: a513270a
   Type: CRC32
  Checksum: 28d05d8a280183817b34186ad3f44f61
   Type: MD5
  Checksum: f70e2f92e35f4bf9d27eb778da0ffbbf32a13e7e
   Type: SHA-1