hAPP695SW 转基因及其相关淀粉样蛋白-β 积累对小鼠海马生化途径的影响。
The Impact of the hAPP695SW Transgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways.
机构信息
Department of Chemistry, Oregon State University, Corvallis, OR, USA.
Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
出版信息
J Alzheimers Dis. 2022;85(4):1601-1619. doi: 10.3233/JAD-215084.
BACKGROUND
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain.
OBJECTIVE
To gain a better insight into alterations in major biochemical pathways underlying AD.
METHODS
We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates.
RESULTS
The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice.
CONCLUSION
Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse.
背景
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是大脑中淀粉样β（Aβ）肽的积累。
目的
深入了解 AD 主要生化途径的变化。
方法
我们比较了表达家族性 AD 相关 hAPP695SW 转基因的 20 月龄雌性 Tg2576 小鼠和其 20 月龄野生型雌性同窝仔鼠海马组织的代谢组学图谱。
结果
hAPP695SW 转基因导致 Aβ在大脑中的过度产生和积累。在 180 个注释代谢物中，有 54 个代谢物存在差异（Tg2576 海马组织中 30 个升高，24 个降低），与氨基酸、核酸、甘油磷脂、神经酰胺和脂肪酸代谢有关。我们的结果表明：1）代谢活性增强，表现为尿素水平升高、脂肪酸β氧化增强和脂肪酸水平降低；2）氧化还原调节增强；3）在老年 hAPP695SW 转基因小鼠的海马组织中，神经兴奋和抑制代谢物失衡。
结论
综上所述，我们的结果表明，与 AD 相关病理学相关的多种代谢途径的失调以及随之而来的兴奋-抑制失衡是 Tg2576 小鼠的一种致病机制。
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