ApoE4 accelerates the condensate to amyloid transition of tau

Abstract Aberrant liquid to solid transition (LST) of tau is a pathological hallmark of several tauopathies, most notably Alzheimer’s disease (AD). ApoE4 is a major genetic risk factor for AD and has been shown to exacerbatetau pathology, although the underlying mechanismremains unclear. Herewe investigate whether apoE isoforms can influenceamyloid aggregation of tau occurring via the liquid–liquid phase separation (LLPS) pathway by monitoring individual tau condensates in real time using total internal reflection fluorescence microscopy (TIRFM) and confocal microscopy. We find that interaction of apoE with tau condensates is dependent on the lipidation status of apoE. Lipid-free apoE, even at 1:1000 substoichiometric concentrations, arrests growth but promotes ageing of the liquid condensates of tau. The strong effect of apoE is accompanied by its preferential accumulation inside the condensates, lowering of the surface tension and promoting amyloid nucleation. Lipidation of apoE2 and apoE3 diminished its amyloid promoting effects very strongly. However, apoE4 even in the lipidated forms accelerated the liquid to amyloid conversion of the tau condensates considerably. Furthermore, the amyloidogenic effect of apoE4 is correlated with its higher delipidation tendency compared to apoE2 and apoE3. Together, our study suggests that lipid-free apoE promotes tau aggregation via dual mechanisms by increasing condensate surface to volume ratio and by facilitating amyloid nucleation possibly at the condensate interfaces. We hypothesize that enhancing apoE4 lipidation in vivo presents a potential strategy to counteract its pathogenic effects on tau aggregation. Highlights All three lipid-free apoE isoforms strongly affect LLPS of tau even at a sub-stoichiometric (1:1000) ratio. ApoE lowers the surface tension, reduces the size and increases the number of the condensates. ApoE isoforms accelerate LST of the tau condensates. Lipidation reduces the effects of apoE, strongly in apoE2 and apoE3 but less so in apoE4. ApoE4 undergoes spontaneous delipidation faster than apoE3 and apoE2.