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 disorder of elderly individuals, is a prominent comorbidity of Alzheimer disease (AD), and causes vascular cognitive impairment and dementia. Previously, a novel transgenic rat model (rTg-D) was generated that produces human familial CAA Dutch E22Q mutant amyloid β-protein in brain, and hemizygous (HEM) animals develop arteriolar CAA type-2. Presented here, homozygous (HOM) rTg-D rats develop more extensive CAA type-2, accumulating abundant fibrillar amyloid pathology, including parenchymal congophilic plaques and dyshorrhic vascular amyloid. Similar to vascular amyloid, fibrillar amyloid plaques in rTg-D HOM rats are chiefly composed of amyloid β40. The rTg-D HOM rats exhibit strong astrocytic and microglial responses as well as phosphorylated tau accumulating in surrounding dystrophic neurites and early tangle-like structures. Cerebral proteomic analyses revealed rTg-D HEM rats and rTg-D HOM rats share some common differentially expressed proteins compared with wild-type rats, although the rTg-D HOM animals exhibit many more elevated proteins. Because the parenchymal fibrillar plaques of rTg-D HOM rats are reminiscent of AD, the cerebral proteomes were compared between rTg-D HOM rats and a transgenic rat AD model, indicating that they share 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 extensive CAA type-2 than rTg-D HEM rats coupled with AD-like pathologic features.