HDL mimetics protect Alzheimer's patients carrying APOE ε4 from SARS-CoV-2 invasion

Ruodan Xu; Junwei Gao; Can Cao; Mingfei Shi; Yonghui Zhang; Shihao Hong; Shijie Guo; Menglin Chen; Ping Song; Gaoshuang Fu; Jing Li; Tengxiao Liang; Yingchun Miao; Lu Tang; Jinsheng Yang; Ning Li; Mingdong Dong

doi:10.1016/j.nantod.2023.102051

HDL mimetics protect Alzheimer's patients carrying APOE ε4 from SARS-CoV-2 invasion

Ruodan Xu
, Junwei Gao
, Can Cao
, Mingfei Shi
, Yonghui Zhang
, Shihao Hong
, Shijie Guo
, Menglin Chen
, Ping Song
, Gaoshuang Fu
, Jing Li
, Tengxiao Liang
, Yingchun Miao
, Lu Tang
, Jinsheng Yang
, Ning Li^*
, Mingdong Dong

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

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.

Original language	English
Article number	102051
Journal	Nano Today
Volume	53
Number of pages	18
ISSN	1748-0132
DOIs	https://doi.org/10.1016/j.nantod.2023.102051
Publication status	Published - Dec 2023

Keywords

Alzheimer's disease
APOE
COVID-19
HDL mimetics
SARS-CoV-2
Surfactant protein D

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@article{a33415e25af04bba90da1f189ceb0f20,

title = "HDL mimetics protect Alzheimer's patients carrying APOE ε4 from SARS-CoV-2 invasion",

abstract = "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.",

keywords = "Alzheimer's disease, APOE, COVID-19, HDL mimetics, SARS-CoV-2, Surfactant protein D",

author = "Ruodan Xu and Junwei Gao and Can Cao and Mingfei Shi and Yonghui Zhang and Shihao Hong and Shijie Guo and Menglin Chen and Ping Song and Gaoshuang Fu and Jing Li and Tengxiao Liang and Yingchun Miao and Lu Tang and Jinsheng Yang and Ning Li and Mingdong Dong",

year = "2023",

month = dec,

doi = "10.1016/j.nantod.2023.102051",

language = "English",

volume = "53",

journal = "Nano Today",

issn = "1748-0132",

publisher = "Elsevier B.V.",

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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 - https://www.scopus.com/pages/publications/85176112014

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 -

HDL mimetics protect Alzheimer's patients carrying APOE ε4 from SARS-CoV-2 invasion

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