Transthyretin Accelerates Vascular Aβ Deposition in a Mouse Model of Alzheimer's Disease

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.