Kavli Institute for Systems Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
K.G. Jebsen Centre for Alzheimer's Disease, NTNU, Trondheim, Norway.
J Alzheimers Dis. 2023;95(2):719-733. doi: 10.3233/JAD-230349.
Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer's disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains.
To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease.
Aβ42 immunolabeling of 12 Wistar rat brains (3-18 months of age) and brain sections from six human subjects aged 20-88 years.
In healthy Wistar rats, we find intracellular Aβ42 (iAβ42) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects.
Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42, is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation.
淀粉样蛋白-β（Aβ）是神经元活动的正常产物，包括易聚集的 Aβ42 变体，后者被认为会导致阿尔茨海默病（AD）。关于 AD 的很多知识都来自于对表达突变人类淀粉样蛋白-β前体（AβPP）以增加 Aβ 产生或 Aβ42/40 比值的转基因啮齿动物的研究。然而，对于啮齿动物大脑中 Aβ42 的正常表达知之甚少。
描述 Aβ42 在 Wistar 大鼠整个生命周期中的大脑广泛表达，并将这些发现与无神经疾病的人类大脑相关联。
对 12 只 Wistar 大鼠（3-18 月龄）的大脑进行 Aβ42 免疫标记，并对 6 名年龄在 20-88 岁的人类受试者的大脑切片进行免疫标记。
在健康的 Wistar 大鼠中，我们在所有年龄段的大脑神经元中都发现了细胞内 Aβ42（iAβ42），但不同脑区之间的水平差异很大。最高水平存在于海马 CA1/下托边界旁的海马神经元和内嗅皮层 II 层的神经元中。就内嗅皮层 II 层而言，我们在人类受试者中也发现了同样高水平的 iAβ42。
在 McGill-R-Thy1-APP 型 AD 大鼠模型中，iAβ42 在健康 Wistar 大鼠中的表达主要集中在 iAβ 聚集和 Aβ 斑块最初形成的相同结构中。与这些 AD 模型大鼠相比，野生型 Wistar 大鼠在 Aβ42 方面的差异是数量上的，而不是质量上的。这一点，再加上我们的人类研究结果，表明 McGill 大鼠模型实际上模拟了野生型神经元对 Aβ42 聚集的潜在特异性易感性。
