Parenchymal and Dyshoric Fibrillar Amyloid Pathology in the rTg-D Rat Model of Cerebral Amyloid Angiopathy Type-2.

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.