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Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A.

ABSTRACT: Growing 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.

SUBMITTER: Nguyen TL

PROVIDER: S-EPMC6176987 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A.

Nguyen Thu Lan TL Duchon Arnaud A Manousopoulou Antigoni A Loaëc Nadège N Villiers Benoît B Pani Guillaume G Karatas Meltem M Mechling Anna E AE Harsan Laura-Adela LA Limanton Emmanuelle E Bazureau Jean-Pierre JP Carreaux François F Garbis Spiros D SD Meijer Laurent L Herault Yann Y

Disease models & mechanisms 20180927 9

Growing 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(<i>Dyrk1a</i>), Ts65Dn, Dp1Yey], all expressing an extra copy of <i>Dyrk1a</i> Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three ...[more]

PMID: 30115750

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Project description:Overexpression of Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS-associated phenotypes have been largely unsuccessful. Epigallocatechin-3-gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS-associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue-specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue-specific-sensitive periods when Dyrk1a regulates cellular processes that shape the long-term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

Dataset Information

Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A.

Publications

Correction of cognitive deficits in mouse models of Down syndrome by a pharmacological inhibitor of DYRK1A.

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