X11alpha haploinsufficiency enhances Abeta amyloid deposition in Alzheimer's disease transgenic mice.

The neuronal adaptor protein X11alpha/mint-1/APBA-1 binds to the cytoplasmic domain of the amyloid precursor protein (APP) to modulate its trafficking and metabolism. We investigated the consequences of reducing X11alpha in a mouse model of Alzheimer's disease (AD). We crossed hAPPswe/PS-1DeltaE9 transgenic (AD tg) mice with X11alpha heterozygous knockout mice in which X11alpha expression is reduced by approximately 50%. The APP C-terminal fragments C99 and C83, as well as soluble Abeta40 and Abeta42, were increased significantly in brain of X11alpha haploinsufficient mice. Abeta/amyloid plaque burden also increased significantly in the hippocampus and cortex of one year old AD tg/X11alpha (+/-) mice compared to AD tg mice. In contrast, the levels of sAPPalpha and sAPPbeta were not altered significantly in AD tg/X11alpha (+/-) mice. The increased neuropathological indices of AD in mice expressing reduced X11alpha suggest a normal suppressor role for X11alpha on CNS Abeta/amyloid deposition.