Abstract
ABSTRACTGrowing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a. Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.
Highlights
Down syndrome (DS) results from the trisomy of human chromosome 21 (HSA21)
Leucettines restore cognitive function, assessed in the novel object recognition (NOR) test, through kinase inhibition in three DS mouse models overexpressing DYRK1A To investigate the importance of DYRK1A in cognitive deficits shown by transgenic mouse models of DS, we used a series of low molecular weight pharmacological inhibitors, collectively known as leucettines
To further reveal functional connectivity (FC) signatures of L41 action in Dp1Yey mice we evaluated the connectivity, across the whole brain, for several key brain areas involved in learning and memory [hippocampal CA1 and dentate gyrus (DG) areas, perirhinal cortex (PERI) and anterior cingulate cortex (ACA)]
Summary
Down syndrome (DS) results from the trisomy of human chromosome 21 (HSA21) It is still the most frequent intellectual disability, affecting 1 newborn per 700 births. Children with DS show good socialization skills – encompassing social relations, friendship and leisure activities – they exhibit difficulties in communication abilities, i.e. the daily use of receptive, expressive and written language (Marchal et al, 2016). They experience troubles in daily life skills, such as self-caring, eating, toileting, dressing, behaving safely, and conceptualizing time and money. Improving the intellectual quotient of DS people would allow them to achieve more independence, increase their vigilance and globally improve their quality of life
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