This study aimed to explore the role of lactoferrin (LTF) in atherosclerosis (AS) and its possible mechanisms. Human left coronary artery tissues were collected and divided into control (CON), coronary heart disease (CHD) and sudden coronary death (SCD) groups. Pathologic changes (including changes in the coronary plaque area, necrotic core, collagen fibers, and foam cell content) were observed. The LTF, P62, and 4-hydroxynonenal (4-HNE) expression levels were assessed. The ApoE^–/– AS mouse model was established. The pathological changes and related protein levels were analyzed after autophagy inhibition. The foam cell model was constructed using an ox-LDL-induced human monocyte line, THP-1. The LTF, BECN1, LC3-II/I, AMP-activated protein kinase (AMPK)/the mammalian target of rapamycin (mTOR) pathway proteins, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and 4-HNE expressions were then detected after silencing of LTF or BECN1. Plaque stability was significantly lower in the SCD group compared to the non-SCD group (p < 0.05). LTF, P62 and 4-HNE levels in plaques increased as plaque stability decreased, and LTF was significantly correlated with plaque progression and autophagy levels. Autophagy inhibition by U0126 leads to the worsening of aortic luminal stenosis, increased necrotic core and foam cell deposits, decreased autophagosomes, reduced LTF expression, and upregulated P62 expression in AS mice. It was further demonstrated that LTF expression correlates with autophagy. LTF expression was increased in ox-LDL-treated THP-1 cells, and silencing BECN1 and/or LTF increased mTOR phosphorylation and 4-HNE levels, inhibited BECN1 and LC3 II expression and AMPK activation, and simultaneously decreased the Bcl-2/Bax ratio. LTF might alleviate AS pathology through accelerating the AMPK/mTOR pathway, and suggested that LTF may be a potential predictive molecule for AS.

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.