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

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.

C-Type Natriuretic Peptide Ameliorates Vascular Injury and Improves Neurological Outcomes in Neonatal Hypoxic-Ischemic Brain Injury in Mice

“…The process was recorded by an overhead camera and analyzed offline. The travel distance was calculated by analyzing the recorded video using NIH image J software with the MouBeAT plugin as previously reported [59,60].…”

YTHDF3 modulates the Cbln1 level by recruiting BTG2 and is implicated in the impaired cognition of prenatal hypoxia offspring

“…reported that antenatal hypoxia increased the susceptibility of Alzheimer’s disease (AD) in the offspring of 5xFAD mice. 54 Similarly, we also discovered diminished cognitive performance in PH offspring through MWM, NOR, and step-through tests, however, the process requires further investigation. The hippocampus, which is required for spatial and episodic memory, is disrupted early in AD.…”

Unravelling the Collective Calcium Dynamics of Physiologically Aged Astrocytes under a Hypoxic State In Vitro

“…In addition, hypoxia has been identified as a significant contributor to the development of age-related neurodegenerative processes [20] since the brain is highly dependent on a continuous oxygen supply to sustain cellular homeostasis and energy metabolism. Hypoxic damage initiates accelerated cell aging [21,22]. Therefore, the functional response of cells to hypoxic exposure should be studied in the context of age-related changes.…”