Robust neuroinflammation and perivascular pathology in rTg-DI rats, a novel model of microvascular cerebral amyloid angiopathy

Abstract

Background: Cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease of the aged and a prominent comorbidity of Alzheimer's disease (AD). CAA can promote a variety of vascular-related pathologies including neuroinflammation, cerebral infarction, and hemorrhages, which can all contribute to vascular cognitive impairment and dementia (VCID). Our understanding of the pathogenesis of CAA remains limited and further investigation of this condition requires better preclinical animal models that more accurately reflect the human disease. Recently, we generated a novel transgenic rat model for CAA (rTg-DI) that develops robust and progressive microvascular CAA, consistent microhemorrhages and behavioral deficits. Methods: In the current study, we investigated perivascular pathological processes that accompany the onset and progressive accumulation of microvascular CAA in this model. Cohorts of rTg-DI rats were aged to 3 months with the onset of CAA and to 12 months with advanced stage disease and then quantitatively analyzed for progression of CAA, perivascular glial activation, inflammatory markers, and perivascular stress. Results: The rTg-DI rats developed early-onset and robust accumulation of microvascular amyloid. As the disease progressed, rTg-DI rats exhibited increased numbers of astrocytes and activated microglia which were accompanied by expression of a distinct subset of inflammatory markers, perivascular pericyte degeneration, astrocytic caspase 3 activation, and disruption of neuronal axonal integrity. Conclusions: Taken together, these results demonstrate that rTg-DI rats faithfully mimic numerous aspects of human microvascular CAA and provide new experimental insight into the pathogenesis of neuroinflammation and perivascular stress associated with the onset and progression of this condition, suggesting new potential therapeutic targets for this condition. The rTg-DI rats provide an improved preclinical platform for developing new biomarkers and testing therapeutic strategies for microvascular CAA.