Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington’s Disease Mice

Abstract

BackgroundDysregulation of iron homeostasis is implicated in the pathogenesis of Huntington’s disease. We have previously shown that increased iron intake in R6/2 HD neonatal mice, but not adult R6/2 HD mice potentiates disease outcomes at 12-weeks of age corresponding to advanced HD [Redox Biol. 2015;4 : 363–74]. However, whether these findings extend to other HD models is unknown. In particular, it is unclear if increased neonatal iron intake can promote neurodegeneration in mouse HD models where disease onset is delayed to mid-adult life.ObjectiveTo determine if increased dietary iron intake in neonatal and adult life-stages potentiates HD in the slowly progressive YAC128 HD mouse model.MethodsFemale neonatal mice were supplemented daily from days 10–17 with 120 μg/g body weight of carbonyl iron. Adult mice were provided diets containing low (50 ppm), medium (150 ppm) and high (500 ppm) iron concentrations from 2-months of age. HD progression was determined using behavioral, brain morphometric and biochemical approaches.ResultsNeonatal-iron supplemented YAC128 HD mice had significantly lower striatal volumes and striatal neuronal cell body volumes as compared to control HD mice at 1-year of age. Neonatal-iron supplementation of HD mice had no effect on rota-rod motor endurance and brain iron or glutathione status. Adult iron intake level had no effect on HD progression. YAC128 HD mice had altered peripheral responses to iron intake compared to iron-matched wild-type controls.ConclusionsFemale YAC128 HD mice supplemented with nutritionally-relevant levels of iron as neonates demonstrate increased striatal degeneration 1-year later.

Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease

“…NIS in R6/2 and YAC128 HD mouse models exacerbates neurodegeneration (Berggren et al, 2015, Berggren et al, 2016. Consistent with this, both N171--82Q HD mice (F (1,61) = 77.70, p < 0.001) and NIS (F (1,61) = 4.28, p = 0.0428) significantly decreased brain weights ( Fig.…”

“…Recommended daily allowances for iron have been developed to prevent iron deficiency, and upper limits were established to avoid short--term adverse effects (Micronutrients, 2001); however, long--term consequences of iron supplementation are not understood (Agrawal et al, 2017). We have previously shown that NIS in R6/2 and YAC128 mouse models of HD exacerbates disease progression (Berggren et al, 2015, Berggren et al, 2016. We have additionally shown that NIS promotes markers of mitochondrial dysfunction in R6/2 mice (Agrawal et al, 2018), although the cell--specific mechanisms by which NIS promotes HD in mice are unknown.…”

LatentToxoplasma gondiiinfection increases soluble mutant huntingtin and promotes neurodegeneration in the YAC128 mouse model of Huntington’s disease

“…They develop striatal and neocortical degeneration, as occurs in human HD [40]. WT and YAC128 HD mice (Jackson Labs) were maintained as described [41]. Mice were housed in OptiMice cages (Animal Care Systems) with 4--5 per cage and one genotype/treatment per cage [39].…”

“…Performance on the rotarod was completed as described [41]. Neurofilament light chain ELISA Neurofilament light chain (NFL) was measured in plasma at 8 and 12 months of age.…”

“…Anaesthetized mice were perfused with 4% (w/v) paraformaldehyde as described [17,41]. Fixed brains were sectioned at 40 µm using a freezing microtome, and serial sections were collected in 12--well plates.…”