Transthyretin accelerates vascular Abeta deposition in a mouse model of Alzheimer's disease

Transthyretin (TTR) binds amyloid-β (Aβ) and prevents Aβ 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 Aβ deposits, tau hyperphosphorylation and apoptosis. TTR is, therefore, speculated to prevent Aβ pathology in AD. However, a role for TTR in Aβ deposition is not yet known. To investigate the relationship between TTR and Aβ 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 Aβ 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 Aβ 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 Aβ deposition in the mouse model of AD.