Elimination of tau tangles and soluble aggregates with the small molecule ACI‐16664 prevents neurodegeneration in vivo
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Abstract INTRODUCTION Pathological tau aggregates are key therapeutic targets in Alzheimer's disease (AD), but current approaches face limitations including poor intracellular penetration, lack of selectivity for aggregated over physiological tau, or reliance on invasive administration. alz71572-sec-0010 METHODS ACI‐16664, an orally available brain penetrant tau aggregation inhibitor, was identified through medicinal chemistry optimization of the Morphomer library and characterized using biochemical assays, neuronal cultures, and the Tg4510 tauopathy mouse model. alz71572-sec-0020 RESULTS ACI‐16664 selectively bound aggregated tau with high apparent affinity, destabilized its β‐sheet structures, blocked intracellular seeding by both soluble and insoluble tau, and prevented tau‐induced neurotoxicity. In Tg4510 mice, ACI‐16664 reduced both soluble tau aggregates and tangles, and prevented neuronal loss, synaptic degeneration, and cortical atrophy. alz71572-sec-0030 DISCUSSION These findings demonstrate the therapeutic value of targeting tau aggregation across its diverse pathological forms and cellular compartments, supporting the potential of this approach to benefit patients with AD and other tauopathies across disease stages. alz71572-sec-0040 Highlights ACI‐16664 is an orally available, CNS‐penetrant small‐molecule inhibitor of tau aggregation. Selectively binds and destabilizes pathological β sheets in tau aggregates Blocks seeding induced by both soluble and insoluble tau
Abstract
Abstract INTRODUCTION Pathological tau aggregates are key therapeutic targets in Alzheimer's disease (AD), but current approaches face limitations including poor intracellular penetration, lack of selectivity for aggregated over physiological tau, or reliance on invasive administration. alz71572-sec-0010 METHODS ACI‐16664, an orally available brain penetrant tau aggregation inhibitor, was identified through medicinal chemistry optimization of the Morphomer library and characterized using biochemical assays, neuronal cultures, and the Tg4510 tauopathy mouse model. alz71572-sec-0020 RESULTS ACI‐16664 selectively bound aggregated tau with high apparent affinity, destabilized its β‐sheet structures, blocked intracellular seeding by both soluble and insoluble tau, and prevented tau‐induced neurotoxicity. In Tg4510 mice, ACI‐16664 reduced both soluble tau aggregates and tangles, and prevented neuronal loss, synaptic degeneration, and cortical atrophy. alz71572-sec-0030 DISCUSSION These findings demonstrate the therapeutic value of targeting tau aggregation across its diverse pathological forms and cellular compartments, supporting the potential of this approach to benefit patients with AD and other tauopathies across disease stages. alz71572-sec-0040 Highlights ACI‐16664 is an orally available, CNS‐penetrant small‐molecule inhibitor of tau aggregation. Selectively binds and destabilizes pathological β sheets in tau aggregates Blocks seeding induced by both soluble and insoluble tau species in neurons Prevents neuronal and synaptic loss and cortical atrophy in Tg4510 tauopathy mice bullet alz71572-list-0001 highlights