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Transthyretin (TTR) binds amyloid-[beta] (A[beta]) and prevents A[beta] fibril formation in vitro. It was reported that the lack of neurodegeneration in a transgenic mouse model of Alzheimer's disease (AD) (Tg2576 mouse) was associated with increased TTR level in the hippocampus, and that chronic infusion of anti-TTR antibody into the hippocampus of Tg2576 mice led to increased local A[beta] deposits, tau hyperphosphorylation and apoptosis. TTR is, therefore, speculated to prevent A[beta] pathology in AD. However, a role for TTR in A[beta] deposition is not yet known. To investigate the relationship between TTR and A[beta] deposition, we generated a mouse line carrying a null mutation at the endogenous TTR locus and the human mutant amyloid precursor protein cDNA responsible for familial AD (Tg2576/TTR-/- mouse) by crossing Tg2576 mice with TTR-deficient mice. We asked whether A[beta] deposition was accelerated in Tg2576/TTR-/- mice relative to the heterozygous mutant Tg2576 (Tg2576/TTR /-) mice. Contrary to our expectations, the degree of total and vascular A[beta] burdens in the aged Tg2576/TTR-/- mice was significantly reduced relative to the age-matched Tg2576/TTR /- mice. Our experiments present, for the first time, compelling evidence that TTR does not suppress but rather accelerates vascular A[beta] deposition in the mouse model of AD.

(C) 2009, International Society of Neuropathology