Priming cell-degradable ubiquitination of Aβ42 with molecular crosstalk

Cell-degradable ubiquitin (Ub) linkages are crucial for breaking down abnormal proteins. However, K48-linked ubiquitination — a canonical Ub linkage driven by a Ub variant that becomes predominant with aging — impedes proteasome function, leading to the accumulation of toxic amyloid-beta 42 (Aβ42) in Alzheimer’s disease (AD). We utilized a catalytic Ub-donating molecule (e.g., lipopolysaccharide, LPS) to induce molecular crosstalk with Aβ42, facilitating oligomeric entrapment to aid the formation of K63-tagged ubiquitin chains—a non-canonical and cell-degradable Ub-tagged linkage—on Aβ42. This entrapment allows oligomers to detour the on-pathway of Aβ42 self-assembly into a transient metastable off-pathway state. Subsequently, a Ub-tagged LPS with an active oxy-ester cap behaved as an intermediate donor that reacted with Lys28 of Aβ42 via a proximity effect, facilitating K63-linked polyubiquitin chain formation. Furthermore, an inhibitor (morin) enhanced the entrapment of oligomers within their local energy minimum during self-assembly, promoting oligomeric efflux and transferring the K63 polyUb-linkage of the LPS intermediate to boost Aβ42 ubiquitination. This K63-linked polyubiquitin was strongly associated with autophagy, a cellular self-digestion mechanism, suggesting that non-canonical polyUb-tagged Aβ42 can be effectively targeted for degradation. Our approach aims to enhance the ubiquitination and subsequent degradation of Aβ42 oligomers, potentially mitigating their accumulation and toxicity in AD.