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

<i>Background:</i> 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. <i>Objectives:</i> 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. <i>Methods:</i> 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. <i>Results:</i> ALC females had higher body weights than controls from 5mo (<i>p</i> &lt; .0001). Controls showed improved recognition memory at 11mo compared with 3mo (<i>p</i> = .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 &lt; .0001); this trended to correlate with recognition memory. <i>Conclusions:</i> 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.

<i>背景：</i>产前酒精暴露（Prenatal alcohol exposure, PAE）会引发行为缺陷，并增加代谢性疾病的患病风险。阿尔茨海默病（Alzheimer’s Disease, AD）是一种神经退行性疾病，代谢性疾病患者罹患该病的风险更高。二者均存在持续性神经炎症反应。
<i>目标：</i>本研究旨在探究产前酒精暴露是否会在3xTg-AD（早老素/淀粉样前体蛋白/tau）小鼠模型中加剧阿尔茨海默病相关的认知衰退，并评估认知功能、代谢损伤与小胶质细胞反应性之间的关联。
<i>方法：</i>酒精暴露组（Alcohol-exposed, ALC）的孕3xTg-AD小鼠自胚胎第8.5天至17.5天，每日接受3 g/kg剂量的酒精暴露。本研究分别于小鼠3月龄（3mo）、7月龄及11月龄时，对每组8~10只雄性和雌性小鼠的识别记忆与联想记忆（恐惧条件反射）进行评估；并于12月龄时检测其葡萄糖耐量、身体成分及海马体小胶质细胞活化情况。
<i>结果：</i>结果显示，自5月龄起，酒精暴露组雌性小鼠的体重显著高于对照组（p < 0.0001）。对照组小鼠在11月龄时的识别记忆能力较3月龄时显著提升（p = 0.007），但酒精暴露组小鼠未出现该现象。相较于幼年小鼠，成年小鼠在恐惧条件反射实验中的冻结行为更强，且酒精暴露组小鼠对恐惧相关线索的反应过度活跃（p = 0.017）。与对照组相比，酒精暴露组雄性小鼠的空腹血糖更低，而雌性小鼠的空腹血糖更高。在酒精暴露组小鼠中，血糖水平与恐惧相关环境的冻结行为得分呈正相关（p = 0.04），体脂量与恐惧相关线索的冻结行为得分亦呈正相关（p = 0.0002）。酒精暴露组小鼠的海马体小胶质细胞活化程度显著高于对照组（p < 0.0001），且该活化程度与识别记忆能力呈潜在相关趋势。
<i>结论：</i>结论表明，酒精暴露组小鼠出现了与年龄相关的认知损伤，该损伤与阿尔茨海默病风险无交互作用，但与代谢功能障碍存在关联，且一定程度上与小胶质细胞活化相关。由此可见，代谢紊乱或可成为胎儿酒精谱系障碍（Fetal Alcohol Spectrum Disorders, FASDs）患者的治疗靶点。