We observed exacerbation of FXS phenotypes in Fmr1KO mice treated with a high dose of anti-Aβ or genetically null for APP (Fmr1KO/AppKO mice) suggesting that over-reduction of APP or a catabolite (presumably Aβ) is as toxic as over-expression likely due to the loss of neuroprotective sAPPα. Here, APP is linked to fragile X syndrome.