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 utero. 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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with cognitive impairment, memory loss, and later dementia among the elderly, which accounts for about 50–75% of all dementia cases (Hebert et al, 2013; Van Cauwenberghe et al, 2016; Jack et al, 2018)
The total entries in the center were significantly increased in 5xFAD offspring exposed to antenatal hypoxia, as compared with normoxia control (Figure 2H)
In correlation with early onset of cognitive decline, we observed significant decrease of cortical synapse markers Synapsin 1 (Syn1) and post-synaptic density protein 95 (PSD95) in 2-month-old 5xFAD offspring exposed to antenatal hypoxia, which occurred in somatosensory and prefrontal cortices of 5xFAD mice at 6 months (Crowe and Ellis-Davies, 2014)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with cognitive impairment, memory loss, and later dementia among the elderly, which accounts for about 50–75% of all dementia cases (Hebert et al, 2013; Van Cauwenberghe et al, 2016; Jack et al, 2018). Large-scale human epidemiological studies have suggested that stress during fetal development and/or in early life may promote cognitive decline and accelerate the onset of AD-like pathology later in life (Wang et al, 2017; Lesuis et al, 2018). Recent animal studies have shown that early life adversity affect AD-like neuropathology, such as Aβ levels and cognition functions at later ages (Sierksma et al, 2013; Zhang et al, 2013; Lesuis et al, 2017)
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