Basic Science and Pathogenesis.

Background: Brain iron dyshomeostasis has been observed in behavioral deficits relevant to neurodegenerative diseases such as Alzheimer's disease (AD), but it remains unclear whether it is a primary cause or an epiphenomenon of disease.

Method: We assessed the effects of brain iron dyshomeostasis on spatial cognition and cognitive flexibility using the IntelliCage system, recognition memory using novel object recognition tasks and anxiety-like behavior using the open field and elevated plus maze tests. We investigated these phenotypes in a HfexTfr2 mouse model of brain iron dyshomeostasis alone (Iron) or combined with an APP/PS1 model of Alzheimer's Aβ amyloidosis (Aβ+Iron), compared with APP/PS1 mice with Aβ amyloidosis alone (Aβ) or wildtype controls.

Result: Brain iron levels in the Iron models were ∼1.5x higher than wildtype control levels at 3 months of age, increasing to ∼1.8x or more at older ages. Brain iron dyshomeostasis alone had no effect on spatial cognition, cognitive flexibility or recognition memory. It moderately accelerated AD-related anxiety-like behavior in males when combined with Aβ, with Aβ+Iron males spending less time in exposed areas of the open field arena than Aβ males at age 6 months (n = 7-13 mice/group/sex, p˂0.05). At this age, irrespective of Aβ status, both male and female mice with brain iron dyshomeostasis also covered less distance in the elevated plus maze (n = 6-10 mice/group/sex, p˂0.0001), while males of this group demonstrated this phenotype in the open field (n = 7-13 mice/group/sex, p˂0.01). This iron-related effect on locomotor activity was diminished by 9 months of age in the open field, with only the male Iron groups covering less distance than the Aβ groups (n = 7-13 mice/group/sex, p = 0.02). Interestingly, at 9 months of age, there was a dramatic reduction in locomotor activity of both Aβ mice and wildtype controls in the elevated plus maze, suggesting brain iron dyshomeostasis drives a natural age-related decline in locomotor activity.

Conclusion: While there was generally no strong effect of brain iron dyshomeostasis on most of the AD-related behavioral phenotypes investigated, there was striking impairment of locomotion, independent of AD-related mutations and amyloidosis. This suggests movement impairment may be an earlier feature of brain iron dyshomeostasis than cognitive decline.