Curtin Health Innovation Research Institute , Curtin University , Bentley , WA 6102 , Australia.
School of Biomedical Sciences , Curtin University , Bentley , WA 6102 , Australia.
ACS Chem Neurosci. 2018 Nov 21;9(11):2774-2785. doi: 10.1021/acschemneuro.8b00193. Epub 2018 Jul 9.
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.
西方社会正面临着一场因老龄化人口中痴呆症发病率上升而引发的健康危机，目前仍缺乏有效的诊断方法，治疗选择有限，也没有治愈方法。衰老（aging）是自然衰老过程中记忆力丧失的最大风险因素，也是阿尔茨海默病等神经退行性疾病的最大风险因素。为了加速开发出改进的诊断方法和治疗方法，我们需要更深入地了解导致健康衰老大脑向痴呆（病理性衰老或阿尔茨海默病）发展的生化途径。不幸的是，许多痴呆症动物模型都模拟了慢性淀粉样前体蛋白的过度表达，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症。一种有前途的动物模型，即衰老加速型小鼠易感品系 8（SAMP8），已被许多研究小组采用来研究大脑衰老过程中发生的生化转变，该模型被报道可模拟加速自然衰老和记忆障碍的机制。传统生化特征分析方法的一个局限性是，许多重要的生化和元素标记物（脂质饱和度、乳酸盐、过渡金属）无法在中或微观空间分辨率下成像。因此，在这项研究中，我们首次对 SAMP8 模型进行了多模态生物光谱学特征描述，并确定了 4 月龄 SAMP8 小鼠与相关对照（SAMR1）小鼠之间重要的生化和元素改变以及共定位。具体来说，我们证明了海马 CA3 区特定亚区存在直接的 Zn 缺乏证据，这与脂质不饱和度降低有关。我们的研究结果还揭示了海马体相邻的胼胝体白质中脂质不饱和度降低和乳酸盐增加的共定位。这些发现可能对未来旨在阐明治疗干预特定生化途径的研究具有重要意义。
