Biospectroscopic Imaging Provides Evidence of Hippocampal Zn Deficiency and Decreased Lipid Unsaturation in an Accelerated Aging Mouse Model
Biospectroscopic Imaging Provides Evidence of Hippocampal Zn Deficiency and Decreased Lipid Unsaturation in an Accelerated Aging Mouse Model
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DOI：
10.1021/acschemneuro.8b00193
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发表时间：
2018-11-01
影响因子：
5
通讯作者：
Hackett, Mark J.
中科院分区：
文献类型：
--
作者：
Fimognari, Nicholas;Hollings, Ashley;Hackett, Mark J.
由于老年人群中痴呆症发病率的增加，西方社会正面临着一场健康流行病，但有效的诊断方法仍然很少，治疗方案也很少，而且无法治愈。衰老是自然衰老过程中记忆丧失的最大危险因素，也是阿尔茨海默病等神经退行性疾病的最大危险因素。为了加速改进诊断和治疗的发展，需要更好地了解驱动健康衰老的大脑走向痴呆症（病理性衰老或阿尔茨海默病）的生化途径。不幸的是，许多痴呆动物模型模拟慢性淀粉样蛋白前体蛋白过表达，尽管这与淀粉样变性和家族性阿尔茨海默病的机制高度相关，但不能很好地模拟自然衰老过程中的痴呆。衰老加速小鼠易感菌株8 （senescence accelerated murine prone strain 8, SAMP8）是研究加速自然衰老和记忆障碍机制的一个很有前景的动物模型，已被许多研究小组用于研究大脑衰老过程中发生的生化转变。传统生化表征方法的一个局限性是，许多重要的生化和元素标记（脂质饱和度、乳酸盐、过渡金属）不能在中尺度或微空间分辨率下成像。因此，在这项研究中，我们首次报道了SAMP8模型的多模态生物光谱表征，并确定了4个月大的SAMP8小鼠和相关对照（SAMR1）小鼠之间重要的生化和元素变化以及共定位。具体来说，我们证明了在海马CA3区特定亚区锌缺乏的直接证据，这些亚区与脂质不饱和度降低共定位。我们的研究结果还揭示了脂质不饱和降低和乳酸盐增加在靠近海马的胼胝体白质中的共定位。这些发现可能对未来旨在阐明治疗干预的特定生化途径的研究具有重要意义。
Western society is facing a health epidemic due to the increasing incidence of dementia in aging populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Aging is the greatest risk factor for memory loss that occurs during the natural aging process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Greater understanding of the biochemical pathways that drive a healthy aging brain toward dementia (pathological aging or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein overexpression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural aging process. A promising animal model reported to model mechanisms of accelerated natural aging and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain aging. A limitation to traditional methods of biochemical characterization is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or microspatial resolution. Therefore, in this investigation, we report the first multimodal biospectroscopic characterization of the SAMP8 model, and have identified important biochemical and elemental alterations, and colocalizations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of Zn deficiency within specific subregions of the hippocampal CA3 sector, which colocalize with decreased lipid unsaturation. Our findings also revealed colocalization of decreased lipid unsaturation and increased lactate in the corpus callosum white matter, adjacent to the hippocampus. Such findings may have important implication for future research aimed at elucidating specific biochemical pathways for therapeutic intervention.