HMGB1 inhibition ameliorates HD knock-in mice phenotype

J. SABA; F. LOPEZ COUSELO; J. BRUNO; M. PALMIERI; M. LASAGA; C. CARUSO

Boston

Simposio; HD2022: Milton Wexler Biennial Symposium; 2022

HD foundation

Huntington disease (HD) is a dominant neurodegenerative disease caused by CAGexpansion in Huntingtin (Htt) gene with progressive loss of striatal neurons resulting incognitive impairment and motor dysfunction. HD pathogenic mechanisms have not beenelucidated yet. HMGB1 is a nuclear protein released from neurons upon exposure to toxicfactors or from activated glial cells, which, once released, can induce inflammation throughRAGE, TLR4, and TLR2 receptors. The expression of RAGE and TLR4 was increased inthe striatum of HD patients. Glycyrrhizin (GLY) is a natural product that binds to andinhibits HMGB1 release from damaged cells and reduces HMGB1 expression. GLY hasneuroprotective effects on traumatic brain injury, neuroinflammation, and Alzheimer’s andParkinson’s diseases. Moreover, GLY administration improves cognitive function of agingmice. However, HMGB1 participation in HD is unknown. Our goal is to determine HMGB1role in HD pathogenesis.Four- and eight-month-old (4M and 8M) zQ175 (HD) knock-in female mice but only 8Mmale HD mice showed motor dysfunction in the open field test. Expression of HMGB1protein was higher in the striatum of 4M and 8M female HD mice whereas no differencewas found in the cortex of the same animals. HMGB1 expression showed decreasedlevels of HMGB1 in 8M HD male mice cortex but increased levels in 8M HD mice malestriatum, indicating that striatal HMGB1 increased expression correlates with motordysfunction. We also found that TLR2 expression was increased in the striatum butdecreased in the cortex of female HD mice whereas TLR2 expression was higher in thecortex and striatum of male HD mice. Also, HD mice exhibited memory deficits at 4M and8M, as shown by reduced exploration of the novel object in the novel object recognitiontest. We next tested whether blocking HMGB1 could modify 4M HD mice phenotype. GLYtreatment (100 mg/kg ip, administered once a day for 15 days) significantly increased thedistance traveled by 4M female HD mice in the open field test. The reduction of thediscrimination index, i.e., low preference for the new object, of HD mice in the NOR testwas prevented by GLY-treatment, indicating that GLY improves memory function.Moreover, GLY treatment decreased HMGB1 expression in the striatum of male andfemale HD mice. Thus, our results suggest that HMGB1 is involved in HD pathogenesisand furthermore that GLY treatment may be beneficial for HD.