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

## TL;DR

This study shows that homozygous rTg-D rats develop severe CAA type-2 and AD-like features, making them a useful model for studying vascular amyloidosis and neurodegeneration.

## Contribution

The study introduces a more severe CAA type-2 rat model with AD-like features for studying vascular amyloidosis and neurodegeneration.

## Key findings

- Homozygous rTg-D rats show more severe CAA type-2 pathology with parenchymal and vascular amyloid accumulation.
- These rats exhibit AD-like features including phosphorylated tau and shared proteomic changes with an AD model.
- Transforming growth factor-β1 signaling and neutrophil swarming are activated in both CAA and AD models.

## 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 dyshoric 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.