Taurine suppresses Aβ aggregation and attenuates Alzheimer's disease pathologies in 5XFAD mice and patient-derived cerebral organoids

Abstract

Alzheimer's disease (AD) is marked by amyloid-beta (Aβ) plaque buildup, tau hyperphosphorylation, neuroinflammation, neuronal loss, and impaired adult hippocampal neurogenesis (AHN). Taurine has shown protective effects in various cellular and animal models of AD, though the molecular mechanisms of free taurine and its effects in patient-derived models remain underexplored. This study evaluates taurine's therapeutic potential using integrated in silico, in vitro, in vivo, and ex vivo approaches. In vitro aggregation assays revealed that taurine (10-100 μM) inhibited Aβ₄₂ fibril formation, with transmission electron microscopy showing looser, amorphous fibrils, particularly at higher doses. Computational simulations further supported that taurine binds stably to Aβ peptide fragments and facilitates the dissociation of Aβ dimers. In HT22 cells, taurine protected against Aβ-induced cytotoxicity. In 5XFAD mice, oral administration of taurine (1000 mg/kg, 4 weeks) significantly reduced Aβ accumulation and hyperphosphorylation of tau at Ser202/Thr205 in the dorsal subiculum. Furthermore, taurine attenuated microgliosis, as evidenced by decreased Iba-1 immunoreactivity, protected against neurodegeneration demonstrated by preserving NeuN-positive neurons, and ameliorated deficit of AHN shown by increasing DCX-positive cells in the subgranular zone of the dentate gyrus. Importantly, in cerebral organoids derived from an AD patient carrying the APOE ε4/ε4 genotype, taurine treatment attenuated Aβ accumulation, decreased tau phosphorylation. These findings highlight taurine's multi-target therapeutic potential targeting amyloid aggregation, tau pathology, neuroinflammation and neurogenesis. Our data support taurine emerges as a promising therapeutic candidate for AD.

Keywords: Adult hippocampal neurogenesis; Alzheimer's disease; Aβ pathology; Cerebral organoids; Molecular docking; Neuroinflammation; Tau hyperphosphorylation; Taurine.