Antenatal Hypoxia Accelerates the Onset of Alzheimer's Disease Pathology in 5xFAD Mouse Model

Authors

Guofang Shen, Department of Basic Sciences, The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, United States.
Shirley Hu, Department of Basic Sciences, The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, United States.Follow
Zhen Zhao, Department of Physiology and Neuroscience, Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Lubo Zhang, Department of Basic Sciences, The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, United States.Follow
Qingyi Ma, Department of Basic Sciences, The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, United States.Follow

Document Type

Article

Publication Date

1-1-2020

Publication Title

Frontiers in aging neuroscience

ISSN

1663-4365

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with cognitive impairment and later dementia among the elderly. Mounting evidence shows that adverse maternal environments during the fetal development increase the risk of diseases later in life including neurological disorders, and suggests an early origin in the development of AD-related dementia (ADRD) . In the present study, we investigated the impact of antenatal hypoxia and fetal stress on the initiation of AD-related pathology in offspring of 5xFAD mice. We showed that fetal hypoxia significantly reduced brain and body weight in the fetal and the early postnatal period, which recovered in young adult mice. Using spontaneous Y-maze, novel object recognition (NOR), and open field (OF) tasks, we found that antenatal hypoxia exacerbated cognitive decline in offspring of 5xFAD compared with normoxia control. Of interest, fetal hypoxia did not alter intraneuronal soluble amyloid-β (Aβ) oligomer accumulation in the cortex and hippocampus in 5xFAD mouse offspring, indicating that antenatal hypoxia increased the vulnerability of the brain to synaptotoxic Aβ in the disease onset later in life. Consistent with the early occurrence of cognitive decline, we found synapse loss but not neuronal death in the cerebral cortex in 5xFAD but not wild-type (WT) offspring exposed to antenatal hypoxia. Furthermore, we also demonstrated that antenatal hypoxia significantly increased microglial number and activation, and reactive astrogliosis in the cerebral cortex in WT offspring. Moreover, antenatal hypoxia resulted in an exacerbated increase of microgliosis and astrogliosis in the early stage of AD in 5xFAD offspring. Together, our study reveals a causative link between fetal stress and the accelerated onset of AD-related pathology, and provides mechanistic insights into the developmental origin of aging-related neurodegenerative disorders.

Volume

12

First Page

251

DOI

10.3389/fnagi.2020.00251

PubMed ID

32973487

Recommended Citation

Shen, Guofang; Hu, Shirley; Zhao, Zhen; Zhang, Lubo; and Ma, Qingyi, "Antenatal Hypoxia Accelerates the Onset of Alzheimer's Disease Pathology in 5xFAD Mouse Model" (2020). Loma Linda University Faculty Publications. 326.
https://scholarsrepository.llu.edu/fac_pubs/326