Prenatal alcohol exposure causes persistent microglial activation and age- and sex- specific effects on cognition and metabolic outcomes in an Alzheimer's Disease mouse model

Background: Prenatal alcohol exposure (PAE) causes behavioral deficits and increases risk of metabolic diseases. Alzheimer's Disease (AD) is a neurodegenerative disease that has a higher risk in adults with metabolic diseases. Both present with persistent neuroinflammation. Objectives: We tested whether PAE exacerbates AD-related cognitive decline in a mouse model (3xTg-AD; presenilin/amyloid precursor protein/tau), and assessed associations among cognition, metabolic impairment, and microglial reactivity. Methods: Alcohol-exposed (ALC) pregnant 3xTg-AD mice received 3 g/kg alcohol from embryonic day 8.5-17.5. We evaluated recognition memory and associative memory (fear conditioning) in 8-10 males and females per group at 3 months of age (3mo), 7mo, and 11mo, then assessed glucose tolerance, body composition, and hippocampal microglial activation at 12mo. Results: ALC females had higher body weights than controls from 5mo (p < .0001). Controls showed improved recognition memory at 11mo compared with 3mo (p = .007); this was not seen in ALC mice. Older animals froze more during fear conditioning than younger, and ALC mice were hyper-responsive to the fear-related cue (p = .017). Fasting blood glucose was lower in ALC males and higher in ALC females than controls. Positive associations occurred between glucose and fear-related context (p = .04) and adiposity and fear-related cue (p = .0002) in ALC animals. Hippocampal microglial activation was higher in ALC than controls (p < .0001); this trended to correlate with recognition memory. Conclusions: ALC animals showed age-related cognitive impairments that did not interact with AD risk but did correlate with metabolic dysfunction and somewhat with microglial activation. Thus, metabolic disorders may be a therapeutic target for people with FASDs.