Bexarotene

Chronic bexarotene treatment was tested in Ts65Dn mice, a model of Down syndrome and Alzheimer’s disease, to see if it reduces amyloid‑beta pathology and improves cognition. Unexpectedly, 9‑week bexarotene administration impaired reference, working, and spatial learning and memory in Ts65Dn mice and also reduced spatial memory in controls. The drug induced marked hypoactivity across multiple behavioral tests. Although hippocampal Aβ1‑40 levels fell, Aβ1‑42 was unaffected. Thyroid analysis revealed significant hypothyroidism with decreased thyroxine and altered TSH in treated animals. The authors conclude that bexarotene‑induced hypothyroidism likely causes the cognitive and behavioral deficits, providing no support for its use in Alzheimer’s disease in Down syndrome.

Fig. 1 Schematic drawing of the MWM protocol, and representative image of the apparatus during the training, and cued sessions. (Vidal V, et al., 2021)

A drug screen using immortalized fibroblasts from patients with multiple sulfatase deficiency (MSD)—a lysosomal disorder caused by SUMF1 mutations—identified the retinoids tazarotene and bexarotene as hits, with arylsulfatase A activity recovery as the primary readout. Treatment of primary MSD fibroblasts and patient‑derived iPSC‑differentiated neuronal progenitor cells increased sulfatase activities, reduced glycosaminoglycan accumulation, and normalized lysosomal position and size. Mechanistically, both drugs increased the stability of variant formylglycine‑generating enzyme. Tazarotene and bexarotene correct MSD pathophysiology, laying the foundation for developing the first therapeutic option for this disorder.

Fig. 2 Tazarotene and bexarotene increase sulfatase activities in MSD primary fibroblasts and MSD iPSC‐derived NPCs. (Schlotawa L, et al., 2023)