Joseph M Schrader, Feng Xu, Xiaoyue Zhu, Mark Majchrzak, Judianne Davis, William E Van Nostrand
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引用次数: 0
Abstract
Cerebral amyloid angiopathy (CAA) is a common age-related disorder, a prominent comorbidity of Alzheimer disease (AD), and causes vascular cognitive impairment and dementia. A previously developed novel transgenic rat model (rTg-D) expresses the human familial CAA Dutch E22Q mutant amyloid β-protein in brain with hemizygous (HEM) animals developing arteriolar CAA type-2 pathology. In this study, homozygous (HOM) rTg-D rats developed more extensive CAA type-2, characterized by abundant fibrillar amyloid accumulation, including parenchymal congophilic plaques and dyshorrhic vascular amyloid. Similar to the vascular amyloid, fibrillar amyloid plaques in rTg-D HOM rats were predominantly composed of amyloid β40. The rTg-D HOM rats exhibited pronounced astrocytic and microglial responses as well as phosphorylated tau accumulating in surrounding dystrophic neurites and early tangle-like structures. Cerebral proteomic analyses revealed that while rTg-D HEM rats and rTg-D HOM rats shared some common differentially expressed proteins compared with wild-type rats, rTg-D HOM rats exhibited many more elevated proteins. Because the parenchymal fibrillar plaques of rTg-D HOM rats resemble those seen in AD, the cerebral proteomes were compared between rTg-D HOM rats and a transgenic rat model of AD. This analysis showed that they shared many differentially expressed proteins and activated pathways, including activation of transforming growth factor-β1 signaling and swarming of neutrophils. In conclusion, the present findings show that rTg-D HOM rats develop more severe CAA type-2 pathology than rTg-D HEM rats coupled with AD-like pathologic features, making them a valuable model for studying the intersection of vascular amyloidosis and neurodegeneration.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.