TY - JOUR
T1 - HDL mimetics protect Alzheimer's patients carrying APOE ε4 from SARS-CoV-2 invasion
AU - Xu, Ruodan
AU - Gao, Junwei
AU - Cao, Can
AU - Shi, Mingfei
AU - Zhang, Yonghui
AU - Hong, Shihao
AU - Guo, Shijie
AU - Chen, Menglin
AU - Song, Ping
AU - Fu, Gaoshuang
AU - Li, Jing
AU - Liang, Tengxiao
AU - Miao, Yingchun
AU - Tang, Lu
AU - Yang, Jinsheng
AU - Li, Ning
AU - Dong, Mingdong
PY - 2023/12
Y1 - 2023/12
N2 - Patients with Alzheimer's disease (AD) inheriting Apolipoprotein (APOE) ε4 are susceptible to COVID-19, but the underlying mechanism of how such a neurodegenerative disease promotes respiratory vulnerability to viral infections remains insufficiently understood. The uncovering of genetic basis of COVID-19 outcome holds the potential to establish disease models for therapeutic development. Here, using human iPSC-derived type II alveolar epithelial cells (hAECII) from AD patients with APOE ε4 and healthy individuals, we showed that AECII of AD had a greater level of SARS-CoV-2 invasion but not replication, along with increased expressions of viral receptor and co-receptors, while reduced pulmonary surfactant proteins. Since low serum HDL-C levels have been implicated in the onset of both AD and COVID-19, we further revealed that HDL mimetics, including 4 F dimeric peptide and its phospholipid conjugate pHDL, were effective in protecting AECII bearing APOE ε4 against SARS-CoV-2 invasion. In AD, concomitant with improved AD pathological phenotypes, HDL mimetics specifically restored the defective basal SP-D, a pulmonary innate immune lipoprotein that targets glycans of the spike protein to neutralize invading viruses. Moreover, HDL mimetics demonstrated strong SP-D-independent virucidal effects, which additionally restricted the entry of coronaviral particles into non-AD AECII models and lungs of human ACE2-transgenic mice in response to Alpha and Omicron variants of SARS-CoV-2. Our work offers critical insights into the respiratory sensitivity of AD patients carrying APOE ε4 to viral infection and repurpose HDL-based therapeutics as potential preventive interventions in respiratory viral pandemics.
AB - Patients with Alzheimer's disease (AD) inheriting Apolipoprotein (APOE) ε4 are susceptible to COVID-19, but the underlying mechanism of how such a neurodegenerative disease promotes respiratory vulnerability to viral infections remains insufficiently understood. The uncovering of genetic basis of COVID-19 outcome holds the potential to establish disease models for therapeutic development. Here, using human iPSC-derived type II alveolar epithelial cells (hAECII) from AD patients with APOE ε4 and healthy individuals, we showed that AECII of AD had a greater level of SARS-CoV-2 invasion but not replication, along with increased expressions of viral receptor and co-receptors, while reduced pulmonary surfactant proteins. Since low serum HDL-C levels have been implicated in the onset of both AD and COVID-19, we further revealed that HDL mimetics, including 4 F dimeric peptide and its phospholipid conjugate pHDL, were effective in protecting AECII bearing APOE ε4 against SARS-CoV-2 invasion. In AD, concomitant with improved AD pathological phenotypes, HDL mimetics specifically restored the defective basal SP-D, a pulmonary innate immune lipoprotein that targets glycans of the spike protein to neutralize invading viruses. Moreover, HDL mimetics demonstrated strong SP-D-independent virucidal effects, which additionally restricted the entry of coronaviral particles into non-AD AECII models and lungs of human ACE2-transgenic mice in response to Alpha and Omicron variants of SARS-CoV-2. Our work offers critical insights into the respiratory sensitivity of AD patients carrying APOE ε4 to viral infection and repurpose HDL-based therapeutics as potential preventive interventions in respiratory viral pandemics.
KW - Alzheimer's disease
KW - APOE
KW - COVID-19
KW - HDL mimetics
KW - SARS-CoV-2
KW - Surfactant protein D
UR - http://www.scopus.com/inward/record.url?scp=85176112014&partnerID=8YFLogxK
U2 - 10.1016/j.nantod.2023.102051
DO - 10.1016/j.nantod.2023.102051
M3 - Journal article
AN - SCOPUS:85176112014
SN - 1748-0132
VL - 53
JO - Nano Today
JF - Nano Today
M1 - 102051
ER -