Jiang Richeng, Shimozawa Makoto, Mayer Johanna, Tambaro Simone, Kumar Rakesh, Abelein Axel, Winblad Bengt, Bogdanovic Nenad, Nilsson Per
Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden.
Department of Otolaryngology Head and Neck Surgery, The First Hospital of Jilin University, Changchun, China.
Front Aging Neurosci. 2022 May 19;14:878303. doi: 10.3389/fnagi.2022.878303. eCollection 2022.
Alzheimer's disease (AD) is characterized by impaired protein homeostasis leading to amyloid-β peptide (Aβ) amyloidosis. Amyloid precursor protein (APP) knock-in mice exhibit robust Aβ pathology, providing possibilities to determine its effect on protein homeostasis including autophagy. Here we compared human AD postmortem brain tissue with brains from two different types of knock-in mice, and mice, exhibiting AD-like pathology. In AD postmortem brains, p62 levels are increased and p62-positive staining is detected in neurons, including potential axonal beadings, as well as in the vasculature and in corpora amylacea. Interestingly, p62 is also increased in the neurons in 12-month-old mice. In brain homogenates from 12-month-old mice, both p62 and light chain 3 (LC3)-II levels are increased as compared to wildtype (WT) mice, indicating inhibited autophagy. Double immunostaining for LC3 and Aβ revealed LC3-positive puncta in hippocampus of 24-month-old mice around the Aβ plaques which was subsequently identified by electron microscopy imaging as an accumulation of autophagic vacuoles in dystrophic neurites around the Aβ plaques. Taken together, autophagy is impaired in knock-in mice upon increased Aβ pathology, indicating that knock-in mouse models provide a platform for understanding the correlation between Aβ and autophagy.
阿尔茨海默病（AD）的特征是蛋白质稳态受损，导致淀粉样β肽（Aβ）淀粉样变性。淀粉样前体蛋白（APP）基因敲入小鼠表现出强烈的Aβ病理特征，为确定其对包括自噬在内的蛋白质稳态的影响提供了可能性。在这里，我们将人类AD死后脑组织与两种不同类型的基因敲入小鼠以及表现出AD样病理特征的小鼠的脑组织进行了比较。在AD死后大脑中，p62水平升高，在神经元中检测到p62阳性染色，包括潜在的轴突串珠，以及在脉管系统和淀粉样体中。有趣的是，在12月龄的小鼠神经元中p62也增加。与野生型（WT）小鼠相比，12月龄小鼠脑匀浆中p62和轻链3（LC3）-II水平均升高，表明自噬受到抑制。对LC3和Aβ进行双重免疫染色，发现在24月龄小鼠海马体中Aβ斑块周围有LC3阳性斑点，随后通过电子显微镜成像确定为Aβ斑块周围营养不良性神经突中自噬空泡的积累。综上所述，在基因敲入小鼠中，随着Aβ病理特征增加，自噬受损，这表明基因敲入小鼠模型为理解Aβ与自噬之间的相关性提供了一个平台。
