Modulation of Amyloid and Tau Aggregation to Alleviate Cognitive Impairment in a Transgenic Mouse Model of Alzheimer's Disease.

Abstract

Aggregation of misfolded amyloid-β (Aβ) and hyperphosphorylated tau proteins to plaques and tangles, respectively, is the major drug target of Alzheimer's disease (AD), as the former is an onset biomarker and the latter is associated with neurodegeneration. Thus, we report a small molecule drug candidate, DN5355, with a dual-targeting function toward aggregates of both Aβ and tau. DN5355 was selected through a series of four screenings assessing 52 chemicals for their functions to inhibit and reverse the aggregation of Aβ and tau by utilizing thioflavin T. When orally administered to AD transgenic mouse model 5XFAD, DN5355 significantly reduced cerebral Aβ plaques and hyperphosphorylated tau tangles. In Y-maze spontaneous alteration and contextual fear conditioning tests, 5XFAD mice showed amelioration of cognitive deficits upon the oral administration of DN5355.