Title: AppSAA mice have blood brain barrier dysfunction and reversible cognitive impairment at 8 months of age

Authors: Cincia Tsai, Eliza Wan, Hita Anand, Prerona Dutta, Isaac Auyeung, Tiffany Zhang, Awab Abdelgadir, William Jagust, Daniela Kaufer

Introduction: Blood brain barrier dysfunction (BBBd) increases in aging and AD, but it remains unclear whether there is a direct link between BBBd and amyloid. AppSAA is a transgenic mouse model that accumulates amyloid plaques from 4 months onwards. IPW is a TGFβ inhibitor that has been shown to reverse BBBd associated neuroinflammation and cognitive impairment in aged wild-type mice. IPW has further been shown to reduce BBB leakage directly in aged wild-type mice. Here, we investigate whether the presence of amyloid plaques accelerates BBBd in mice, and whether IPW treatment in AppSAA mice improves cognition.

Methods: The Barnes Maze, Novel Object Recognition Test, and T maze were used to evaluate spatial memory function. Immunohistochemical staining of beta-amyloid (CT695) and fibrinogen was used to quantify amyloid plaques and BBB leakage, respectively.

Results: 

1. Amyloid plaques accumulate throughout the lifespan of AppSAA mice.

2. AppSAA mice have elevated BBB leakage compared to age-matched controls at 8 months but not at 12 months.

3. IPW treatment in AppSAA mice at 8 months rescues cognitive impairment, but treatment at 12 months does not.

Conclusions: Amyloid plaques are sufficient to cause BBBd. AppSAA mice have increased BBBd compared to controls at 8 months, but this difference is attenuated at 12 months. BBBd intervention timing is crucial. Reversal of BBBd with IPW treatment only rescues cognitive impairment in AppSAA mice at 8 months, when leakage is significantly higher than controls.

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