Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Elimination of tau tangles and soluble aggregates with the small molecule ACI-16664 prevents neurodegeneration in vivo.
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Preitner Nicolas, Dehlinger Véronique, Rodriguez Patrick, Fabbri Kerstin, Varisco Yvan, Pigni Matteo, Lovison Alessandra, Münzenmaier Lucas, Piorkowska Kasia, Fuchs Aline, Ait-Bouziad Nadine, Fournier Nicolas, Jepaul Sandra, Molette Jérôme, Gabellieri Emanuele, Darmency Vincent, Poli Sonia, Pfeifer Andrea, Kosco-Vilbois Marie, Capotosti Francesca
Аннотация
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.
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.
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.
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.
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.
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.
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.