Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Abstract

The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

“…Dyrk1a is upregulated in DS and AD (Ferrer et al, ; Kimura et al, ; Lockstone et al, ), may dysregulate the 3‐repeat tau to 4‐repeat tau ratio (Wegiel, Gong, & Hwang, ), and is part of the triplicated “DS critical region” that has been implicated in cognitive impairment in DS. Importantly, normalizing Dyrk1a gene dosage in trisomic mice improves spatial and reference memory and related AD‐like phenotypes (Altafaj et al, ; Garcia‐Cerro, Rueda, Vidal, Lantigua, & Martinez‐Cue, ; Garcia‐Cerro et al, ), highlighting the importance of attenuating Dyrk1a expression levels in DS as a potential therapeutic approach.…”

“…somic mice improves spatial and reference memory and related AD-like phenotypes(Altafaj et al, 2013;Garcia-Cerro, Rueda, Vidal, Lantigua, & Martinez-Cue, 2017;Garcia-Cerro et al, 2014), highlighting the importance of attenuating Dyrk1a expression levels in DS as a potential therapeutic approach.There are also several downregulated genes involved in AD/DS pathology normalized in Ts65Dn1 mice, including Bace1. Although associated with b-cleavage of APP, leading to greater Ab and bCTF expression, attenuation of Bace1 levels by MCS may indicate a counterintuitive normalization of APP processing in vulnerable neurons that reflects the importance of steady-state Ab and bCTF levels, underscor-…”

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

“…The primary antibodies used were a guinea pig anti-proDynorphin (ppDyn, 1:500; Neuromics, Minneapolis, MN, USA) to label D1-type MSNs [27], a mouse antiEnkephalin (Enk, 1:100; Abcam, Cambridge, UK) to label D2-type MSNs [28], a goat antiChAT to label cholinergic interneurons (1:100; Millipore, Billerica, MA, USA; [29]), a rabbit anti-phospho-Ser240/244-rpS6 (1:1000, Cell Signaling Technology, Beverly, MA, USA) and a rabbit anti-phospho-Ser235/236-rpS6 (1:200, Cell Signaling Technology). Primary antibodies were detected by using Alexa Fluor-594 and Alexa Fluor-488 conjugated secondary antibodies (1:1.000; Life Technologies, Eugene, OR, USA).…”

“…It is widely accepted that binding of risperidone to DRD2s antagonizes the indirect pathway [26][27][28][29][30][31][32]. Thus, we examined whether the DRD2-enriched MSNs, identified with antibodies to enkephalin (Enk+), showed any differences in rpS6 activation between strains, as well as in response to risperidone.…”

Neuronal overexpression ofDYRK1A/minibrainalters motor decline, neurodegeneration and synaptic plasticity inDrosophila

“…However, the contribution of DYRK1A overexpression to the faster age-dependent decline in cognitive and motor function in DS is unclear. It is predicted to play a role as Dyrk1a overexpression intensifies with age in the brain of Ts65Dn and Ts1Cje mouse models of DS [12,15,23,24], it is associated with AD-DS-like histopathological changes in the brain of aged Ts65Dn mice [5,25] and it enhances APP processing and the formation of hyperphosphorylated Tau aggregates in rat hippocampal progenitor cells in vitro [26]. The contribution of DYRK1A overexpression to the shorter life expectancy in DS has also not been explored.…”