Role Of Ten Eleven Translocation-2 (Tet2) In Modulating Neuronal Morphology And Cognition In A Mouse Model Of Alzheimer'S Disease
JOURNAL OF NEUROCHEMISTRY(2021)
Abstract
Abnormal expression of Ten eleven translocation-2 (Tet2) contributes to the pathogenesis of Alzheimer's disease (AD). However, to date, the role of Tet2 in modulating neuronal morphology upon amyloid-beta (A beta)-induced neurotoxicity has not been shown in a mouse model of AD. Here, we have developed a model of injured mouse hippocampal neurons induced by A beta(42) oligomers in vitro. We also investigated the role of Tet2 in injured neurons using recombinant plasmids-induced Tet2 inhibition or over-expression. We found that the reduced expression of Tet2 exacerbated neuronal damage, whereas the increased expression of Tet2 was sufficient to protect neurons against A beta(42) toxicity. Our results indicate that the brains of aged APPswe/PSEN1 double-transgenic (2 x Tg-AD) mice exhibit an increase in A beta plaque accumulation and a decrease in Tet2 expression. As a result, we have also explored the underlying mechanisms of Tet2 in cognition and amyloid load in 2 x Tg-AD mice via adeno-associated virus-mediated Tet2 knockdown or over-expression. Recombinant adeno-associated virus was microinjected into bilateral dentate gyrus regions of the hippocampus of the mice. Knocking down Tet2 in young 2 x Tg-AD mice resulted in the same extent of cognitive dysfunction as aged 2 x Tg-AD mice. Importantly, in middle-aged 2 x Tg-AD mice, knocking down Tet2 accelerated the accumulation of A beta plaques, whereas over-expressing Tet2 alleviated amyloid burden and memory loss. Furthermore, our hippocampal RNA-seq data, from young 2 x Tg-AD mice, were enriched with aberrantly expressed lncRNAs and miRNAs that are modulated by Tet2. Tet2-modulated lncRNAs (Malat1, Meg3, Sox2ot, Gm15477, Snhg1) and miRNAs (miR-764, miR-211, and miR-34a) may play a role in neuron formation. Overall, these results indicate that Tet2 may be a potential therapeutic target for repairing neuronal damage and cognitive impairment in AD.
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Key words
Alzheimer's disease, cognitive impairment, lncRNAs, miRNAs, neuronal morphology, Tet2 protein
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