Sex differences are a well-known phenomenon in Alzheimer's disease (AD), with women having a higher risk for AD than men. Many AD mouse models display a similar sex-dependent pattern, with females showing earlier cognitive deficits and more severe neuropathology than males. However, whether those differences are relevant to human disease is unclear. Here we show that in AD mouse models that overexpress amyloid precursor protein (APP) under control of the prion protein promoter (PrP), female transgenic mice have higher APP expression than males, complicating interpretations of the role of sex-related factors in such models. By contrast, in a tTa:APPsi model, in which APP expression is driven by the tetracycline transactivator (tTa) from the CaMKIIα promoter, there are no sex-related differences in expression or processing of APP. In addition, the levels of Aβ dimers and tetramers, as well as Aβ peptide accumulation, are similar between sexes. Behavioral testing demonstrated that both male and female tTa:APPsi mice develop age-dependent deficits in spatial recognition memory and conditional freezing to context. These cognitive deficits were accompanied by habituation-associated hyperlocomotion and startle hyper-reactivity. Significant sex-related dimorphisms were observed, due to females showing earlier onsets of the deficits in conditioned freezing and hyperlocomotion. In addition, tTa:APPsi males but not females demonstrated a lack of novelty-induced activation. Both males and females showed atrophy of the dentate gyrus (DG) of the dorsal hippocampus, associated with widening of the pyramidal layer of the CA1 area in both sexes. Ventral DG was preserved. Sex-related differences were limited to the DG, with females showing more advanced degeneration than males. Collectively, our data show that the tTa:APPsi model is characterized by a lack of sex-related differences in APP expression, making this model useful in deciphering the mechanisms of sex differences in AD pathogenesis. Sex-related dimorphisms observed in this model under conditions of equal APP expression between sexes suggest a higher sensitivity of females to the effects of APP and/or Aβ production.

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