ApoE isoforms differentially regulate neuronal membrane proteasomes to shift the threshold for pathological aggregation of endogenous Tau

Neuronal membrane proteasomes (NMPs) are a functionally transmembrane subset of 20S proteasomes that degrade newly synthesized proteins. To date, the molecular composition of NMPs is undefined, and moreover, whether NMPs can influence any aspect of protein aggregation with relevance to neurodegenerative disorders remains unexplored. Using a Cre-dependent conditional knock-in mouse line to endogenously tag the proteasome, we find that NMPs co-purify with ApoE. We discover that NMP membrane localization is differentially modulated by ApoE isoforms (E4 less than E3 less than E2) in vitro, in vivo, and in human postmortem samples. This isoform-dependent change in NMP localization inversely correlates with the risk that ApoE isoforms pose for Alzheimers Disease. ApoE4-dependent reduction of NMP localization is strongest in brain regions selectively vulnerable to neurodegeneration. We synthesized selective NMP-specific inhibitors and discovered that NMP inhibition induces aggregation of endogenous and newly synthesized mouse and human Tau isoforms, without the need for seeding or pathogenic mutations. We posit that newly synthesized Tau is exceptionally susceptible to aggregation due to NMP dysfunction. Stereotactic injection of NMP inhibitors in vivo induces aggregation, phosphorylation, somatodendritic mislocalization and pathology of endogenous newly synthesized Tau. Finally, using ApoE-KI/hTau-KI crosses, we find that ApoE isoforms differentially shift the aggregation threshold for Tau. Overall, our data define NMPs as a pivotal proteostasis mechanism underlying the formation of endogenous Tau aggregates, which is directly regulated by the largest genetic risk factor for late-onset Alzheimers Disease. ### Competing Interest Statement KVR received funding from Eli Lilly.