APOE4 Exacerbates Cerebral Tau Pathology Through Cholesterol‐Induced Degradation of Phosphatase in Atherosclerosis

ABSTRACT Background Apolipoprotein epsilon4 allele (APOE4) is a common risk factor for atherosclerosis (AS) and neurodegenerative diseases like Alzheimer's disease (AD), but whether and how APOE4 induces AD‐like neuropathies in the brain of AS pathology remains poorly characterized. Methods By combining postmortem AS human brains and APOE4 knock‐in mice, we examined the effects of APOE4 on tau and related neuropathological changes in the brain of AS. Behavioral and pathological observations were used to evaluate the protective effects of facilitating cholesterol transport in APOE4 AS mice. Results Here, we showed that APOE4 carriers exhibited higher AD‐like phosphorylated Tau (p‐Tau) levels in AS postmortem brains. Knocking in human APOE4 in high fat diet‐fed mice induced AS pathology and coupled AS and AD. APOE4 promoted cerebral cholesterol content, which could trigger protein phosphatase 2A (PP2A) degradation. We further demonstrated cholesterol could facilitate the ubiquitination of PP2A B and PP2A C, which were regulatory and catalytic subunits of PP2A respectively, leading to PP2A B and PP2A C degradation through the ubiquitin‐proteasome system. Reduced PP2A B and PP2A C resulted in cerebral Tau hyperphosphorylated at multiple AD‐associated sites. The APOE4 AS mice exhibited an AD‐like phenotype, including synaptic degeneration, blood‐brain barrier breakdown, glial activation, and cognitive impairment simultaneously. Pharmacologically facilitating cholesterol transport alleviated neuropathologies in APOE4 AS mice. Conclusion Altogether, these results suggested a role of the APOE4 in linking AS with Tau neuropathology, which might increase the risk of related neurodegenerative diseases for AS patients.