Thioflavin-positive tau aggregates complicating quantification of amyloid plaques in the brain of 5XFAD transgenic mouse model.

ABSTRACT

Transgenic mouse models recapitulating Alzheimer's disease (AD) pathology are pivotal in molecular studies and drug evaluation. In transgenic models selectively expressing amyloid-ß (Aß), thioflavin S (ThS), a fluorescent dye with ß-sheet binding properties, is widely employed to observe amyloid plaque accumulation. In this study, we investigated the possibility that a commonly used Aß-expressing AD model mouse, 5XFAD, generates ThS-positive aggregates of ß-sheet structures in addition to Aß fibrils. To test this hypothesis, brain sections of male and female 5XFAD mice were double-stained with ThS and monoclonal antibodies against Aß, tau, or α-synuclein, all of which aggregates are detected by ThS. Our results revealed that, in addition to amyloid plaques, 5XFAD mice express ThS-positive phospho-tau (p-tau) aggregates. Upon administration of a small molecule that exclusively disaggregates Aß to 5XFAD mice for six weeks, we found that the reduction level of plaques was smaller in brain sections stained by ThS compared to an anti-Aß antibody. Our findings implicate that the use of ThS complicates the quantification of amyloid plaques and the assessment of Aß-targeting drugs in 5XFAD mice.