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Alzheimer’s disease (AD) and anxiety are two concurrent disorders often co-existing in older adults. Interestingly, women are more likely to experience anxiety than men in both general population and AD. To date, the mechanisms underlying the gender differences in the pathogenesis of AD and anxiety disorder are still not clear. Previously, we have found that the deletion of vacuolar protein sorting 10 protein (VPS10P)-domain containing receptor/sortilin (encoded by Sort1 gene) increases anxiety-like behavior but does not affect cognition in both sexes of 3-month-old mice in an open field test and an elevated plus maze test; and females tended to show a more severe anxious phenotype. In this study, in order to examine the role of sortilin in the gender-dependent anxiety-like behavior with age under normal condition or physical illness like AD, we recruited both sexes of 9-month-old WT, Sort1-/-, APP/PS1 (mouse model of AD), and Sort1-/-APP/PS1 mice to perform the open field test and Morris water maze test. Our data showed that aged female but not male mice deficient in Sort1 with or without the transgenes of APP and PS1 displayed a significant increase in anxiety-like behavior as shown by decreased percentage of time in central zone in the open field test. Our data also showed that only female APP/PS1 or Sort1-/-APP/PS1 mice showed hyperactivities and anxiety-like behavior. Sort1 deficiency did not affect cognitive behavior in both sexes of aged wild type or transgenic AD mice. The present study found a gender-specific role of sortilin in regulation of anxiety-like behaviors in aged mice, which could be a potential mechanism involved in gender differences of anxiety disorders.

Female Wild-Type and APP/PS1 Transgenic Mice Deficient in Sort1 Are Prone to Anxiety-Like Behavior at Older Ages