Lei Yun, Nougaisse Jayvon, Malek Maryam, Mishu Miskatul M, Bai Yu, Denney Kirstyn, Du Quansheng, Stranahan Alexis M, Garza Jacob C, Lu Xin-Yun
Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.
Mol Psychiatry. 2025 Jun 4. doi: 10.1038/s41380-025-03067-0.
Aging and genetic predisposition are the primary risk factors for Alzheimer's disease (AD), while chronic stress represents a modifiable risk factor that can accelerate aging and drive AD progression. However, the complex interplay between aging, chronic stress and genetic underpinnings in AD pathogenesis remains poorly understood. Notably, cognitive phenotyping in AD mouse models has yielded inconsistent results. In this study, we characterized the age-dependent trajectory of phenotypes in 5xFAD mice on a congenic C57BL/6 J background. These mice harbor five familial AD (FAD)-related mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes. Aβ plaque deposition was detected in specific brain regions by 4 months of age, but cognitive performance remained intact at this stage. However, by 8-9 months, these mice developed impairments in spatial working memory, novel object recognition memory, and social recognition memory. By 11 months, they also showed metabolic alterations, including lower body weight, higher energy expenditure and increased locomotor activity. Furthermore, after 10 days of chronic social isolation-unpredictable stress, 4-month-old 5xFAD mice exhibited cognitive deficits, accompanied by increased Aβ accumulation in the medial prefrontal cortex, hippocampus, and entorhinal cortex. In contrast, age- and sex-matched wild-type littermate controls subjected to the same stress paradigm showed no significant cognitive changes. These observations suggest that Aβ deposition increases stress vulnerability in 5xFAD mice. We conclude that the phenotypic expression of AD-related gene mutations, including pathological changes and cognitive decline, progresses with age and can be induced by chronic psychological stress, underscoring the interactive effects of stress, aging, and genetic vulnerability on disease onset and severity.
衰老和遗传易感性是阿尔茨海默病（AD）的主要风险因素，而慢性应激是一个可改变的风险因素，可加速衰老并推动AD进展。然而，衰老、慢性应激和AD发病机制中的遗传基础之间的复杂相互作用仍知之甚少。值得注意的是，AD小鼠模型中的认知表型分析结果并不一致。在本研究中，我们对同源C57BL/6 J背景下的5xFAD小鼠的表型随年龄变化的轨迹进行了表征。这些小鼠在淀粉样前体蛋白（APP）和早老素1（PSEN1）基因中携带五个家族性AD（FAD）相关突变。在4个月大时，在特定脑区检测到Aβ斑块沉积，但此时认知能力仍保持完好。然而，到8-9个月时，这些小鼠在空间工作记忆、新物体识别记忆和社会识别记忆方面出现损伤。到11个月时，它们还表现出代谢改变，包括体重减轻、能量消耗增加和运动活动增加。此外，在经历10天的慢性社会隔离-不可预测应激后，4个月大的5xFAD小鼠表现出认知缺陷，同时内侧前额叶皮质、海马体和内嗅皮质中的Aβ积累增加。相比之下，接受相同应激范式的年龄和性别匹配的野生型同窝对照小鼠没有出现明显的认知变化。这些观察结果表明，Aβ沉积增加了5xFAD小鼠的应激易感性。我们得出结论，AD相关基因突变的表型表达，包括病理变化和认知衰退，随年龄增长而进展，并且可由慢性心理应激诱导，强调了应激、衰老和遗传易感性对疾病发生和严重程度的交互作用。
