Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

Abstract

Data shows that inflammation during pregnancy significantly exerts a long-term influence on offspring, such as increasing the risk of adult cognition decline in animals. However, it is unclear whether gestational inflammation affects the neurobehavioral and neurobiochemical outcomes in the motherself during aging. In this study, pregnant CD-1 mice intraperitoneally received lipopolysaccharide (LPS) in two doses (25 and 50 g/kg, respectively) or normal saline daily during gestational days 15-17. At the age of 15 months, a battery of behavioral tasks was employed to evaluate their species-typical behaviors, sensorimotor ability, anxiety levels, and spatial learning and memory abilities. An immunohistochemical method was utilized preliminarily to detect neurobiochemical indicators consisting of amyloid-β, p h o s p h o r y l a t e d t a u , p r e s y n a p t i c p r o t e i n s synaptotagmin-1 and syntaxin-1, glial fibrillary acidic protein (GFAP), and histone-4 acetylation on the K8 site (H4K8ac). The behavioral results showed that LPS exposure during pregnancy exacerbated a decline in 15-month-old CD-1 mice's abilities to nest, their sensorimotor and spatial learning and memory capabilities, and increased their anxiety levels. The neurobiochemical results indicated that gestational LPS exposure also intensified age-related hippocampal changes, including increased amyloid-β 42 , phosphorylated tau, synaptotagmin-1 and GFAP, and decreased syntaxin-1 and H4K8ac. Our results suggested that the inflammatory insult during pregnancy could be an important risk factor for the development of Alzheimer's disease, and the H4K8 acetylation might play an important role in the underlying mechanism. This study offers a perspective for improving strategies that support healthy development and successful aging.

Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer‐like behavioral and neuropathological changes in CD‐1 mice

“…Bacterial infections during pregnancy result in a systemic inflammatory reaction in mothers and can affect cognition in their offspring. Our recent findings suggested that age significantly affected spatial learning and memory from middle age to old age in CD‐1 mice, and maternal exposure to LPS in CD‐1 mice could trigger and exacerbate the age‐related spatial memory impairment in their offspring from middle age onwards in a linear manner (Li, Cao, et al, ; Li, Wang, et al, ). In the current study, we used the same system to mimic maternal systemic inflammation during pregnancy and examined its long‐term effect on recognition and spatial learning and memory in their offspring.…”

“…The behavioral experiments including nesting, open field, beam walking, elevated plus maze, OLR, and RAWM were conducted according to our previous studies (Chen et al, ; Li, Cao, et al, ; Li, Wang, et al, ; Tong et al, ).…”

“…The strept–avidin–biotin–peroxidase complex (SABC) method was performed as described in our previous studies (Li, Cao, et al, ; Li, Wang, et al, ; Tong et al, ). The main difference is that primary antibodies including rabbit monoclonal anti‐Aβ 42 (1:300) and polyclonal anti‐p‐tauser404 (1:500) and GFAP (1:500) were purchased from the Abcam and Dako.…”

“…Besides behavioral and cognitive dysfunctions, maternal infection insult by LPS can lead to certain changes in hippocampal morphology and neurochemistry in offspring, such as neuron loss, altered synaptic transmission, reduced hippocampal neurogenesis, decreased expression of synaptophysin, and increased expression of GFAP in the hippocampal CA1 region (Boksa, ; Graciarena, Depino, & Pitossi, ; Hao et al, ; Lowe, Luheshi, & Williams, ). A recent investigation by our group showed that maternal inflammatory insult by LPS administration during pregnancy worsened the age‐related hippocampal neurobiological indicators (decreased H4K8ac, H3K9ac, and Stx‐1 and increased Syt‐1) in the offspring of CD‐1 mice from midlife (12 months old) to the twilight years (22 months old; Li, Cao, et al, ; Li, Wang, et al, ). However, these previous studies did not comprehensively assess cognitive and behavioral functions in these mice suffered with LPS during late embryogenesis at different age especially old age, nor did they detect AD‐related pathophysiology in the hippocampus.…”

“…with LPS 0.79 mg/kg at gestational days (gd) 8, 10, and 12 showed distinct learning and memory decline in their offspring at the ages of 10 and 20 months but not 3 months (Hao, Hao, Li, & Li, ). Our previous studies indicated that pregnant CD‐1 mice intraperitoneally received 50 μg/kg LPS during gd 15–17 accelerated age‐related learning and memory impairment and species‐typical behaviors in middle‐aged offspring (Chen et al, ; Li, Cao, et al, ; Li, Wang, et al, ). Moreover, this LPS effect on learning and memory deficit was also observed in old‐aged offspring mice and thus was even a lower‐dose injection of LPS (25 μg/kg; Li, Cao, et al, ; Li, Wang, et al, ).…”