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

ABSTRACT

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.

KEYWORDS:

• Alzheimer’s disease
• fetal alcohol syndrome
• metabolic syndrome
• aging
• glucose tolerance
• obesity
• developmental origins of health and disease
• cognitive performance
• neuroinflammation
• microglia

Acknowledgements

The authors thank George Flentke, Alyson Selchick, and Carolyn A. Munson for their assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/00952990.2022.2119571

Additional information

Funding

This work was supported by NIH awards R01 AA024980 (SMM), AA024980-S1 (SMM), AA022413 (SMM), AA011085 (SMS), AA022999 (SMS), P30 DK056350 (UNC Nutrition Obesity Research Center), and internal funds from the UNC NRI.