Browsing by Author "Dhillon, Hardeep"

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    Effects of Epigallcatechin-3-gallate in Novel Object Recognition of Ts65Dn Down Syndrome Mice
    (Office of the Vice Chancellor for Research, 2015-04-17) Minhas, Saniya; Abeysekera, Irushi; Delgado, Fatima; Dhillon, Hardeep; Goodlett, Charles R.; Roper, Randall J.
    Down syndrome (DS) is one of the most common genetic disorders and has an incidence of 1/700 births; which can lead to many impairments, both physically and mentally. All individuals with DS have cognitive impairments which results in learning and memory deficits. To study these deficits, we use the Ts65Dn mouse model that carries trisomy of approximately 50% of the genes found on human chromosome 21. DYRK1A, a gene found in three copies in both humans with DS and Ts65Dn mice has been shown to have increased expression in the brains of humans with DS. DYRK1A protein is involved in a number of critical pathways including CNS development. Epigallcatechin-3-gallate (EGCG), the main polyphenolic compound found in green tea, inhibits DYRK1A. We hypothesize that EGCG treatment help improve cognitive deficits in trisomic mice. After treatment, the mice were subjected to behavioral tasks, including the Novel Object Recognition (NOR) test. Our results indicate that there was a significant difference that existed due to trisomy in Ts65Dn mice; but there was no significant effect of a low dose EGCG treatment. Further studies are examining the effects of the NOR task after a higher dose EGCG treatment.
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    Effects of Epigallocatechin-3-gallate Treatment on Cognitive Deficits in a Down Syndrome Mouse Model
    (Office of the Vice Chancellor for Research, 2014-04-11) Dhillon, Hardeep; Abeysekera, Irushi S.; Stringer, Megan
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in a constellation of phenotypes that include intellectual disability (ID) and skeletal abnormalities. Ts65Dn mice, the most extensively studied model of DS, have three copies of approximately half the genes on Hsa21 and display many DS related phenotypes including skeletal and ID deficits. DYRK1A is found in three copies both in humans with DS and in Ts65Dn mice; DYRK1A has increased expression in humans with DS and is involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallcatechin-3-gallate (EGCG), the main polyphenolic compound found in green tea, inhibits Dyrk1a activity, and we have shown previously that a three-week treatment with EGCG during adolescence normalizes some skeletal abnormalities in Ts65Dn mice. The current study tested the hypothesis that a similar 3-week treatment with EGCG will also rescue cognitive deficits observed in Ts65Dn mice. Trisomic mice and euploid littermates were given EGCG or water (control) for three weeks during adolescence. Following termination of the treatment, the mice were tested sequentially (over 5 weeks) on locomotor activity (two daily 30-min sessions in an activity chamber), novel object recognition (NOR) memory, acquisition of delayed non-matching to place (DNMP) spatial working memory in a tmaze, or spatial learning and memory in the Morris water maze (MWM). Results to date indicate that Ts65Dn mice exhibit deficits in the learning and memory tasks compared to controls, but the 3-week EGCG treatment did not significantly improve their performance.We hypothesize that for EGCG to be effective for improving cognitive deficits of the Ts65Dn mice, it needs to be present in the brain during the behavioral testing period; our ongoing studies are testing this with continuous EGCG treatment throughout the behavioral testing process.
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    Effects of Increased Dosage EGCG Treatment on Cognitive Deficits in the Ts65Dn Down Syndrome Mouse Model
    (Office of the Vice Chancellor for Research, 2015-04-17) Dhillon, Hardeep; Abeysekera, Irushi; Stringer, Megan; Goodlett, Charles R.; Roper, Randall J.
    Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the leading genetic cause of cognitive impairment and results in a constellation of phenotypes. Although symptomatic and therapeutic treatments exist for some DS phenotypes, treatments generally do not address the genetic etiology. The Ts65Dn mouse model, which contains a triplication of approximately half the gene orthologs of Hsa21, exhibits hippocampal learning and memory deficits as well as cerebellar motor and spatial deficits similar to those present in individuals with DS. DYRK1A, one of the genes overexpressed in DS, has been identified as a potential cause of cognitive impairment; therefore normalization of DYRK1A activity may be a valid form of treatment. We have shown that Epigallocatechin-3-gallate (EGCG), a major polyphenol of green tea, can rescue skeletal deficits found in the Ts65Dn mouse model at a low dosage. When this same low dosage was used to rescue behavioral deficits, however, it was ineffective. We hypothesize that high dose EGCG treatment lasting throughout the behavioral testing period will rescue the cognitive deficits observed in Ts65Dn mice. Trisomic mice and euploid littermates were given EGCG or water (control) for 7 weeks while being tested sequentially on novel object recognition (NOR) and Morris water maze (MWM). Our current data set shows that Ts65Dn mice exhibit deficits in learning and memory; further data will be collected in order to identify the effect of EGCG. Data showing pure EGCG as being ineffective will suggest the importance adding a supplemental compound, while data showing pure EGCG as an effective form of treatment will strongly support use of EGCG in translational studies in individuals with Down syndrome.