ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation

Significance In Alzheimer’s disease (AD), BACE1 links the key molecular alterations with toxic Aβ overload, and pharmacological regulation of BACE1 may facilitate the discovery of novel mechanisms. We report such a small-molecule conophylline (CNP) that inhibits BACE1 translation through the 5′ untranslated region (5′UTR). Mediated by its target ARL6IP1, the brain-penetrating CNP attenuates amyloidogenesis and rescues cognitive decline in APP/PS1 mice. Upon CNP treatment, an enhanced interaction of ARL6IP1 with FXR1, which is identified as the 5′UTR-targeted protein, allows to sequester FXR1 from the 5′UTR, leading to the reduced translation of BACE1. Collectively, whereas CNP exhibits a therapeutic potential for AD through ARL6IP1, a dynamic FXR1–RNA interaction in the translational control of BACE1 is highlighted.

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