School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China.
Laboratory Animal Resource Center, Capital Medical University, Beijing, China.
Aging Cell. 2021 Jun;20(6):e13380. doi: 10.1111/acel.13380. Epub 2021 May 25.
Amyloid-β (Aβ) deposits, pathologic tau, and neurodegeneration are major pathological hallmarks of Alzheimer's disease (AD). The relationship between neuronal loss and Aβ deposits is one of the fundamental questions in the pathogenesis of AD. However, this relationship is controversial. One main reason for the conflicting results may be the confounding effects of pathologic tau, which often coexists with Aβ deposits in the brains of AD patients. To clarify the relationship between neuronal loss and Aβ deposits, mouse models of AD, which develop abundant Aβ deposits in the aged brain without pathologic tau, were used to examine the co-localization of NeuN-positive neurons, NF-H-positive axons, MBP-positive myelin sheaths, and Aβ deposits. Neuronal loss, as measured by decreased staining of the neuronal cell body, axon, and myelin sheath, as well as the IBA-1-positive microglia, was significantly increased in the core area of cerebral Aβ deposits, but not in adjacent areas. Furthermore, neuronal loss in the core area of cerebral Aβ deposits was correlated with Aβ deposit size. These results clearly indicate that neuronal loss is restricted to the core of Aβ deposits, and this restricted loss probably occurs because the Aβ deposit attracts microglia, which cluster in the core area where Aβ toxicity and neuroinflammation toxicity are restrained. These findings may contribute to our understanding of the relationship between neuronal loss and Aβ deposits in the absence of pathologic tau.
淀粉样蛋白-β（Aβ）沉积、病理性 tau 蛋白和神经退行性变是阿尔茨海默病（AD）的主要病理学特征。神经元丢失与 Aβ 沉积之间的关系是 AD 发病机制中的基本问题之一。然而，这种关系存在争议。导致结果冲突的一个主要原因可能是病理性 tau 蛋白的混杂效应，在 AD 患者的大脑中，Aβ 沉积通常与病理性 tau 蛋白共存。为了阐明神经元丢失与 Aβ 沉积之间的关系，使用在老年大脑中产生丰富 Aβ 沉积而没有病理性 tau 蛋白的 AD 小鼠模型，来检查 NeuN 阳性神经元、NF-H 阳性轴突、MBP 阳性髓鞘和 Aβ 沉积的共定位。在大脑 Aβ 沉积核心区域，神经元细胞体、轴突和髓鞘的染色减少，以及 IBA-1 阳性小胶质细胞的神经元丢失显著增加，但在相邻区域没有增加。此外，大脑 Aβ 沉积核心区域的神经元丢失与 Aβ 沉积大小相关。这些结果清楚地表明，神经元丢失仅限于 Aβ 沉积的核心区域，这种局限的丢失可能是因为 Aβ 沉积吸引了小胶质细胞，小胶质细胞在 Aβ 毒性和神经炎症毒性受到限制的核心区域聚集。这些发现可能有助于我们理解在没有病理性 tau 蛋白的情况下神经元丢失与 Aβ 沉积之间的关系。
