HMBG1 Inhibition Ameliorates HD Knock-In Mice Phenotype / Motor and Cognitive Dysfunction

JULIETA SABA; FEDERICO LÓPEZ COUSELO; JULIETA BRUNO; MATEO PALMIERI; MERCEDES LASAGA; CARLA CARUSO

Boston

Congreso; HD2022: Milton Wexler Biennal Symposium; 2022

HD Foundation

Huntington disease (HD) is a dominant neurodegenerative disease caused by CAG expansion in Huntingtin (Htt) genewith progressive loss of striatal neurons resulting in cognitive impairment and motor dysfunction. HD pathogenicmechanisms have not been elucidated yet. HMGB1 is a nuclear protein released from neurons upon exposure to toxicfactors or from activated glial cells, which, once released, can induce inflammation through RAGE, TLR4, and TLR2receptors. The expression of RAGE [2, 3] and TLR4 was increased in the striatum of HD patients [4]. Glycyrrhizin (GLY)is a natural product that binds to and inhibits HMGB1 release from damaged cells and reduces HMGB1 expression [8].GLY has neuroprotective effects on traumatic brain injury, neuroinflammation, and Alzheimer’s and Parkinson’s diseases[8]. Moreover, GLY administration improves cognitive function of aging mice [11]. However, HMGB1 participation in HD isunknown. Our goal is to determine HMGB1 role in HD pathogenesis. Four- and eight-month-old (4M and 8M) zQ175(HD) knock-in female mice but only 8M male HD mice showed motor dysfunction in the open field test. In these animals,expression of HMGB1 protein was higher in the striatum of 4M and 8M female HD mice whereas no difference was foundin the cortex of the same animals. HMGB1 expression showed decreased levels of HMGB1 in 8M HD male mice cortexbut increased levels in 8M HD mice male striatum, indicating that striatal HMGB1 increased expression correlates withmotor dysfunction. We also found that TLR2 expression was increased in the striatum but decreased in the cortex offemale HD mice whereas TLR2 expression was higher in the cortex and striatum of male HD mice. Also, HD miceexhibited memory deficits at 4M and 8M, as shown by reduced exploration of the novel object in the novel objectrecognition test. We next tested whether blocking HMGB1 could modify 4M HD mice phenotype. GLY treatment (100 mg/kg ip, administered once a day for 15 days) significantly increased the distance traveled by 4M female HD mice. TheNOR test showed that HD mice had low discrimination index, i.e., low preference for the new object, effect that wasprevented by GLY-treatment, indicating that GLY improves memory function. Regarding HMGB1 expression, GLYtreatment decrease it in the striatum of male and female HD mice. Thus, our results suggest that HMGB1 is involved inHD pathogenesis and furthermore that GLY treatment may be beneficial for HD.